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Lettau K, Forchhammer S, Fehrenbacher B, Mahmutovic L, Scharpf M, Blumenstock G, Schaller M, Bonzheim I, Khozooei S, Toulany M. The subcellular distribution of phosphorylated Y-box-binding protein-1 at S102 in colorectal cancer patients, stratified by KRAS mutational status and clinicopathological features. Mol Oncol 2025. [PMID: 40420381 DOI: 10.1002/1878-0261.70060] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2025] [Revised: 04/03/2025] [Accepted: 05/13/2025] [Indexed: 05/28/2025] Open
Abstract
Oncoprotein Y-box-binding protein-1 (YB-1) is involved in all cancer hallmarks. One of the most studied post-translational modifications of YB-1 is phosphorylation on Serine 102 (S102), which is involved in cancer progression. KRAS mutations are frequent, have been associated with poor prognosis and therapy resistance, and they are considered a major stimulator of S102 YB-1 in vitro. In this study, a relationship between S102 YB-1 phosphorylation in subcellular fractions and KRAS mutation was investigated in CRC tissues, and its association with clinicopathological parameters was analyzed. Immunohistochemistry on 36 patient samples and 5 normal tissue samples highlighted nuclear S102 YB-1 was specific to cancer tissues. Nuclear S102 YB-1 was expressed in 47.2% of tumor tissues, which was positively correlated with KRAS mutation (P = 0.017). There was no significant association between cytoplasmic S102 YB-1 with KRAS mutation status (P = 0.391). Further studies in larger cohorts are needed to validate the observed results. The significant association between S102 YB-1 in the nucleus and KRAS mutation may suggest YB-1 as an effective target to improve survival of CRC patients with KRAS-mutated tumors.
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Affiliation(s)
- Konstanze Lettau
- Department of Radiation Oncology, University Hospital Tuebingen, Tuebingen, Germany
- Department of Internal Medicine I, University Hospital Tuebingen, Tuebingen, Germany
| | - Stephan Forchhammer
- Department of Dermatology, University Hospital Tuebingen, Tuebingen, Germany
| | - Birgit Fehrenbacher
- Department of Dermatology, University Hospital Tuebingen, Tuebingen, Germany
| | - Lejla Mahmutovic
- Institute of Pathology and Neuropathology, University Hospital Tuebingen, Tuebingen, Germany
| | - Marcus Scharpf
- Institute of Pathology and Neuropathology, University Hospital Tuebingen, Tuebingen, Germany
| | - Gunnar Blumenstock
- Department of Clinical Epidemiology and Biostatistics, University Hospital Tuebingen, Tuebingen, Germany
| | - Martin Schaller
- Department of Dermatology, University Hospital Tuebingen, Tuebingen, Germany
| | - Irina Bonzheim
- Institute of Pathology and Neuropathology, University Hospital Tuebingen, Tuebingen, Germany
| | - Shayan Khozooei
- Department of Radiation Oncology, University Hospital Tuebingen, Tuebingen, Germany
| | - Mahmoud Toulany
- Department of Radiation Oncology, University Hospital Tuebingen, Tuebingen, Germany
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Takeda M, Yoshida S, Inoue T, Sekido Y, Hata T, Hamabe A, Ogino T, Miyoshi N, Uemura M, Yamamoto H, Doki Y, Eguchi H. The Role of KRAS Mutations in Colorectal Cancer: Biological Insights, Clinical Implications, and Future Therapeutic Perspectives. Cancers (Basel) 2025; 17:428. [PMID: 39941797 PMCID: PMC11816235 DOI: 10.3390/cancers17030428] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2024] [Revised: 01/17/2025] [Accepted: 01/23/2025] [Indexed: 02/16/2025] Open
Abstract
Background/Objectives: Colorectal cancer (CRC) remains a leading cause of cancer mortality globally, with KRAS mutations occurring in 30-40% of cases, contributing to poor prognosis and resistance to anti-EGFR therapy. This review explores the biological significance, clinical implications, and therapeutic targeting of KRAS mutations in CRC. Methods: A comprehensive analysis of the existing literature and clinical trials was performed, highlighting the role of KRAS mutations in CRC pathogenesis, their impact on prognosis, and recent advancements in targeted therapies. Specific attention was given to emerging therapeutic strategies and resistance mechanisms. Results: KRAS mutations drive tumor progression through persistent activation of MAPK/ERK and PI3K/AKT signaling pathways. These mutations influence the tumor microenvironment, cancer stem cell formation, macropinocytosis, and cell competition. KRAS-mutant CRC exhibits poor responsiveness to anti-EGFR monoclonal antibodies and demonstrates primary and acquired resistance to KRAS inhibitors. Recent breakthroughs include the development of KRAS G12C inhibitors (sotorasib and adagrasib) and promising agents targeting G12D mutations. However, response rates in CRC remain suboptimal compared to other cancers, necessitating combination therapies and novel approaches, such as vaccines, nucleic acid-based therapeutics, and macropinocytosis inhibitors. Conclusions: KRAS mutations are central to CRC pathogenesis and present a significant therapeutic challenge. Advances in KRAS-targeted therapies offer hope for improved outcomes, but resistance mechanisms and organ-specific differences limit efficacy. Continued efforts in personalized treatment strategies and translational research are critical for overcoming these challenges and improving patient survival.
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Affiliation(s)
- Mitsunobu Takeda
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan
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Zou H, Li S, Guo J, Wen L, Lv C, Leng F, Chen Z, Zeng M, Xu J, Li Y, Li X. Pan-cancer analysis reveals age-associated genetic alterations in protein domains. Am J Hum Genet 2025; 112:44-58. [PMID: 39708814 PMCID: PMC11739924 DOI: 10.1016/j.ajhg.2024.11.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2024] [Revised: 11/26/2024] [Accepted: 11/26/2024] [Indexed: 12/23/2024] Open
Abstract
Cancer incidence and mortality differ among individuals of different ages, but the functional consequences of genetic alterations remain largely unknown. We systematically characterized genetic alterations within protein domains stratified by affected individual's age and showed that the mutational effects on domains varied with age. We further identified potential age-associated driver genes with hotspots across 33 cancers. The candidate drivers involved numerous cancer-related genes that participate in various oncogenic pathways and play central roles in human protein-protein interaction (PPI) networks. We found widespread age biases in protein domains and identified the associations between hotspots and age. Age-stratified PPI networks perturbed by hotspots were constructed to illustrate the function of mutations enriched in domains. We found that hotspots in young adults were associated with premature senescence. In summary, we provided a catalog of age-associated hotspots and their perturbed networks, which may facilitate precision diagnostics and treatments for cancer.
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Affiliation(s)
- Haozhe Zou
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, Heilongjiang 150081, China
| | - Si Li
- School of Interdisciplinary Medicine and Engineering, Harbin Medical University, Harbin 150081, China
| | - Jiyu Guo
- School of Interdisciplinary Medicine and Engineering, Harbin Medical University, Harbin 150081, China
| | - Luan Wen
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, Heilongjiang 150081, China
| | - Chongwen Lv
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, Heilongjiang 150081, China
| | - Feng Leng
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, Heilongjiang 150081, China
| | - Zefeng Chen
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, Heilongjiang 150081, China
| | - Mengqian Zeng
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, Heilongjiang 150081, China
| | - Juan Xu
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, Heilongjiang 150081, China
| | - Yongsheng Li
- School of Interdisciplinary Medicine and Engineering, Harbin Medical University, Harbin 150081, China.
| | - Xia Li
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, Heilongjiang 150081, China.
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Gelfer R, Gulla A, Kalvin HL, Song Y, Harding J, Abou-Alfa GK, O'Reilly EM, Park W, Chandwani R, Wei A, Kingham P, Drebin J, Balachandran V, D'Angelica M, Soares K, Gonen M, Jarnagin WR. KRAS Variants Are Associated With Survival Outcomes and Genomic Alterations in Biliary Tract Cancers. JCO Precis Oncol 2024; 8:e2400263. [PMID: 39642327 DOI: 10.1200/po.24.00263] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2024] [Revised: 09/02/2024] [Accepted: 10/29/2024] [Indexed: 12/08/2024] Open
Abstract
PURPOSE KRAS variants are associated with poor outcomes in biliary tract cancers (BTCs). This study assesses the prevalence of KRAS variants and their association with survival and recurrence in patients with intrahepatic cholangiocarcinoma (IHC), extrahepatic cholangiocarcinoma (EHC), and gallbladder adenocarcinoma (GB). METHODS In this cross-sectional, single-institution study at Memorial Sloan Kettering, tumors from 985 patients treated between 2004 and 2022 with IHC, EHC, and GB who underwent either curative-intent resection or were treated with chemotherapy for unresectable disease were used for targeted sequencing. RESULTS Of the 985 patients sequenced, 15% had a KRAS mutation. Five hundred and seventy-two had unresectable disease (n = 395 IHC, n = 71 EHC, n = 106 GB) and 413 were treated with curative-intent resection (n = 175 IHC, n = 119 EHC, and n = 119 GB). Median follow-up time was 18 months (IQR, 11-31). KRAS G12D mutations were most common in IHC (38%) and EHC (37%) tumors. Mutations in SF3B1 co-occurred with mutant KRAS in IHC and EHC, with comutant resectable patients having worse survival after adjusting for tumor type (hazard ratio [HR], 4.04 [95% CI, 1.45 to 11.2]; P = .007). KRAS G12 mutations were associated with worse survival in patients with IHC compared with wild-type (WT) or other KRAS mutations, regardless of resection status (unresectable P < .001, resectable P = .011). After adjusting for clinical covariates, KRAS G12 mutations remained a prognostic indicator for patients with IHC compared with WT (HR, 1.99 [95% CI, 1.41 to 2.80]; P < .001). CONCLUSION The adverse impact of KRAS mutations in BTC is driven by G12 alterations in patients with IHC regardless of resection status, which was not observed in GB or EHC. There are unique comutational partners in distinct BTC subsets. These differences have important clinical implications in the era of KRAS-targeted therapeutics.
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Affiliation(s)
- Rebecca Gelfer
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Aiste Gulla
- Department of Surgery, Vilnius University Hospital, Vilnius, Lithuania
| | - Hannah L Kalvin
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Yi Song
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY
| | - James Harding
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
- Department of Medicine, Weill Cornell Medicine, New York, NY
| | - Ghassan K Abou-Alfa
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
- Department of Medicine, Weill Cornell Medicine, New York, NY
- Trinity School of Medicine, Trinity College Dublin, Dublin, Ireland
| | - Eileen M O'Reilly
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
- Department of Medicine, Weill Cornell Medicine, New York, NY
| | - Wungki Park
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
- Department of Medicine, Weill Cornell Medicine, New York, NY
| | | | - Alice Wei
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY
- Department of Medicine, Weill Cornell Medicine, New York, NY
| | - Peter Kingham
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY
- Department of Medicine, Weill Cornell Medicine, New York, NY
| | - Jeffrey Drebin
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY
- Department of Medicine, Weill Cornell Medicine, New York, NY
| | | | - Michael D'Angelica
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY
- Department of Medicine, Weill Cornell Medicine, New York, NY
| | - Kevin Soares
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY
- Department of Medicine, Weill Cornell Medicine, New York, NY
| | - Mithat Gonen
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY
| | - William R Jarnagin
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY
- Department of Medicine, Weill Cornell Medicine, New York, NY
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Ekmekciu I, Zucha DM, Christmann J, Wisser S, Heuer V, Sargin B, Hollerbach S, Lamberti C, Müller L, Lugnier C, Verdoodt B, Denz R, Terzer T, Feder I, Reinacher-Schick A, Tannapfel A, Tischoff I. Exploring the molecular profile of localized colon cancer: insights from the AIO Colopredict Plus registry. Front Oncol 2024; 14:1434791. [PMID: 39628993 PMCID: PMC11612501 DOI: 10.3389/fonc.2024.1434791] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2024] [Accepted: 09/11/2024] [Indexed: 12/06/2024] Open
Abstract
Introduction Understanding the mutational landscape of colon cancer (CC) is crucial for targeted therapy development. Microsatellite instability (MSI-H), rat sarcoma (RAS), and B-Raf proto-oncogene, serine/threonine kinase (BRAF) mutations (MT) are pivotal markers. Further investigation into clinicopathological features of RAS and BRAF MT in microsatellite stable (MSS) and MSI-H tumors is warranted. Methods A retrospective analysis of 4883 localized CC patients (pts.) was conducted. Molecular profiling assessed MSI, KRAS, NRAS, and BRAF MT. Correlation with clinicopathological data employed ANOVA and Chi-square tests. Disease-free survival (DFS) and overall survival (OS) were analyzed adjusting for age, gender, sidedness, UICC stage, Charlson Comorbidity Index (CCI). A Cox model incorporated all variables as covariates. Results This analysis included 4883 pts. (2302 female/2572 male, 3865 (79.2%) MSS, 1018 (20.8%) MSI-H). MSS pts. had more All-Wild Type (WT), KRAS MT, and NRAS MT tumors vs. MSI-H pts. (42.1% vs. 21.1%; 39.8% vs. 15.4%; 3.6% vs. 0.7%; p<0.001 for each). BRAF MT tumors (95.5% BRAF V600E MT) were more prevalent in MSI-H individuals (62.8% vs. 8.1%, p<0.001). KRAS and BRAF MT tumors were more frequently right-sided, while BRAF MT tumors were associated with female gender, advanced disease stage, lymph node positivity, and poorer differentiation in the MSS subset (p<0.001). Common KRAS mutations included p.G12D (30.44%) and p.G12V (21.3%) in MSS and p.G13D (28.9%) and p.G12D (22.37%) in MSI-H. NRAS MT tumors were dominated by codon 61 mutations (51.7%). Survival analysis revealed worst prognosis in BRAF MT MSS tumors (DFS: HR 1.74 (95% CI 1.15-2.62, p=0.009; OS: HR 1.61 (95% CI 0.99-2.6), p=0.055). The 3-years DFS and 5-years OS rates were lowest in this subset (61.6% and 57.7% respectively). Discussion These findings highlight the complex interplay between molecular subtypes, clinicopathological features, and survival outcomes in early CC. Further research is needed to elucidate underlying mechanisms and develop personalized treatment strategies.
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Affiliation(s)
- Ira Ekmekciu
- Department of Hematology, Oncology and Palliative Care, St. Josef Hospital, Ruhr University, Bochum, Germany
| | | | | | - Sarah Wisser
- Institute of Pathology, Ruhr University, Bochum, Germany
| | - Vera Heuer
- Department of Hematology, Oncology and Palliative Care, St. Josef Hospital, Ruhr University, Bochum, Germany
| | - Buelent Sargin
- Hematology and Medical Oncology, St-Marien-Hospital Lunen, Lunen, Germany
| | - Stephan Hollerbach
- Department of Gastroenterology, Allgemeines Krankenhaus (AKH) Celle, Celle, Germany
| | | | | | - Celine Lugnier
- Department of Hematology, Oncology and Palliative Care, St. Josef Hospital, Ruhr University, Bochum, Germany
| | | | - Robin Denz
- Department of Medical Informatics, Biometrics and Epidemiology, Ruhr University, Bochum, Germany
| | - Tobias Terzer
- Department of Hematology, Oncology and Palliative Care, St. Josef Hospital, Ruhr University, Bochum, Germany
| | - Inke Feder
- Institute of Pathology, Ruhr University, Bochum, Germany
| | - Anke Reinacher-Schick
- Department of Hematology, Oncology and Palliative Care, St. Josef Hospital, Ruhr University, Bochum, Germany
| | | | - Iris Tischoff
- Institute of Pathology, Ruhr University, Bochum, Germany
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Yang X, Wu H. RAS signaling in carcinogenesis, cancer therapy and resistance mechanisms. J Hematol Oncol 2024; 17:108. [PMID: 39522047 PMCID: PMC11550559 DOI: 10.1186/s13045-024-01631-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2024] [Accepted: 11/01/2024] [Indexed: 11/16/2024] Open
Abstract
Variants in the RAS family (HRAS, NRAS and KRAS) are among the most common mutations found in cancer. About 19% patients with cancer harbor RAS mutations, which are typically associated with poor clinical outcomes. Over the past four decades, KRAS has long been considered an undruggable target due to the absence of suitable small-molecule binding sites within its mutant isoforms. However, recent advancements in drug design have made RAS-targeting therapies viable, particularly with the approval of direct KRASG12C inhibitors, such as sotorasib and adagrasib, for treating non-small cell lung cancer (NSCLC) with KRASG12C mutations. Other KRAS-mutant inhibitors targeting KRASG12D are currently being developed for use in the clinic, particularly for treating highly refractory malignancies like pancreatic cancer. Herein, we provide an overview of RAS signaling, further detailing the roles of the RAS signaling pathway in carcinogenesis. This includes a summary of RAS mutations in human cancers and an emphasis on therapeutic approaches, as well as de novo, acquired, and adaptive resistance in various malignancies.
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Affiliation(s)
- Xiaojuan Yang
- Liver Digital Transformation Research Laboratory, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, Sichuan, 610041, P.R. China
| | - Hong Wu
- Liver Digital Transformation Research Laboratory, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, Sichuan, 610041, P.R. China.
- Liver Transplantation Center, Liver Digital Transformation Research Laboratory, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, Sichuan, 610041, P.R. China.
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Hálková T, Bunganič B, Traboulsi E, Minárik M, Zavoral M, Benešová L. Prognostic Role of Specific KRAS Mutations Detected in Aspiration and Liquid Biopsies from Patients with Pancreatic Cancer. Genes (Basel) 2024; 15:1302. [PMID: 39457426 PMCID: PMC11507146 DOI: 10.3390/genes15101302] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2024] [Revised: 09/28/2024] [Accepted: 10/03/2024] [Indexed: 10/28/2024] Open
Abstract
Background/Objectives: Although the overall survival prognosis of patients in advanced stages of pancreatic ductal adenocarcinoma (PDAC) is poor, typically ranging from days to months from diagnosis, there are rare cases of patients remaining in therapy for longer periods of time. Early estimations of survival prognosis would allow rational decisions on complex therapy interventions, including radical surgery and robust systemic therapy regimens. Understandably, there is great interest in finding prognostic markers that can be used for patient stratification. We determined the role of various KRAS mutations in the prognosis of PDAC patients using biopsy samples and circulating tumor DNA. Methods: A total of 118 patients with PDAC, clinically confirmed by endoscopic ultrasound-guided fine-needle aspiration biopsy (EUS-FNB), were included in the study. DNA was extracted from cytological slides following a standard cytology evaluation to ensure adequacy (viability and quantity) and to mark the tumor cell fraction. Circulating tumor DNA (ctDNA) was extracted from plasma samples of 45 patients in stage IV of the disease. KRAS mutations in exons 12 and 13 were detected by denaturing capillary electrophoresis (DCE), revealing a minute presence of mutation-specific heteroduplexes. Kaplan-Meier survival curves were calculated for individual KRAS mutation types. Results:KRAS mutations were detected in 90% of tissue (106/118) and 44% of plasma (20/45) samples. All mutations were localized at exon 2, codon 12, with G12D (GGT > GAT) being the most frequent at 44% (47/106) and 65% (13/20), followed by other types including G12V (GGT > GTT) at 31% (33/106) and 10% (2/20), G12R (GGT > CGT) at 17% (18/106) and 10% (2/20), G12C (GGT/TGT) at 5% (5/106) and 0% (0/20) and G12S (GGT/AGT) at 1% (1/106) and 5% (1/20) in tissue and plasma samples, respectively. Two patients had two mutations simultaneously (G12V + G12S and G12D + G12S) in both types of samples (2%, 2/106 and 10%, 2/20 in tissue and plasma samples, respectively). The median survival of patients with the G12D mutation in tissues was less than half that of other patients (median survival 101 days, 95% CI: 80-600 vs. 228 days, 95% CI: 184-602), with a statistically significant overall difference in survival (p = 0.0080, log-rank test), and furthermore it was less than that of all combined patients with other mutation types (101 days, 95% CI: 80-600 vs. 210 days, 95% CI: 161-602, p = 0.0166). For plasma samples, the survival of patients with this mutation was six times shorter than that of patients without the G12D mutation (27 days, 95% CI: 8-334 vs. 161 days, 95% CI: 107-536, p = 0.0200). In contrast, patients with detected KRAS G12R in the tissue survived nearly twice as long as other patients in the aggregate (286 days, 95% CI: 70-602 vs. 162 days, 95% CI: 122-600, p = 0.0374) or patients with other KRAS mutations (286 days, 95% CI: 70-602 vs. 137 days, 95% CI: 107-600, p = 0.0257). Conclusions: Differentiation of specific KRAS mutations in EUS-FNB and ctDNA (above all, the crucial G12D and G12R) is feasible in routine management of PDAC patients and imperative for assessment of prognosis.
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Affiliation(s)
- Tereza Hálková
- Centre for Applied Genomics of Solid Tumors (CEGES), Genomac Research Institute, Drnovská 1112/60, 161 00 Prague, Czech Republic
- Department of Biochemistry, Faculty of Science, Charles University, Hlavova 8/2030, 128 00 Prague, Czech Republic
| | - Bohuš Bunganič
- Department of Medicine, First Faculty of Medicine, Charles University and Military University Hospital, U Vojenské Nemocnice 1200, 169 02 Prague, Czech Republic
| | - Eva Traboulsi
- Department of Pathology, Military University Hospital Prague, U Vojenské Nemocnice 1200, 169 02 Prague, Czech Republic
| | - Marek Minárik
- Department of Analytical Chemistry, Faculty of Science, Charles University, Hlavova 8/2030, 128 00 Prague, Czech Republic;
| | - Miroslav Zavoral
- Department of Medicine, First Faculty of Medicine, Charles University and Military University Hospital, U Vojenské Nemocnice 1200, 169 02 Prague, Czech Republic
| | - Lucie Benešová
- Centre for Applied Genomics of Solid Tumors (CEGES), Genomac Research Institute, Drnovská 1112/60, 161 00 Prague, Czech Republic
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Healy FM, Turner AL, Marensi V, MacEwan DJ. Mediating kinase activity in Ras-mutant cancer: potential for an individualised approach? Front Pharmacol 2024; 15:1441938. [PMID: 39372214 PMCID: PMC11450236 DOI: 10.3389/fphar.2024.1441938] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2024] [Accepted: 09/06/2024] [Indexed: 10/08/2024] Open
Abstract
It is widely acknowledged that there is a considerable number of oncogenic mutations within the Ras superfamily of small GTPases which are the driving force behind a multitude of cancers. Ras proteins mediate a plethora of kinase pathways, including the MAPK, PI3K, and Ral pathways. Since Ras was considered undruggable until recently, pharmacological targeting of pathways downstream of Ras has been attempted to varying success, though drug resistance has often proven an issue. Nuances between kinase pathway activation in the presence of various Ras mutants are thought to contribute to the resistance, however, the reasoning behind activation of different pathways in different Ras mutational contexts is yet to be fully elucidated. Indeed, such disparities often depend on cancer type and disease progression. However, we are in a revolutionary age of Ras mutant targeted therapy, with direct-targeting KRAS-G12C inhibitors revolutionising the field and achieving FDA-approval in recent years. However, these are only beneficial in a subset of patients. Approximately 90% of Ras-mutant cancers are not KRAS-G12C mutant, and therefore raises the question as to whether other distinct amino acid substitutions within Ras may one day be targetable in a similar manner, and indeed whether better understanding of the downstream pathways these various mutants activate could further improve therapy. Here, we discuss the favouring of kinase pathways across an array of Ras-mutant oncogenic contexts and assess recent advances in pharmacological targeting of various Ras mutants. Ultimately, we will examine the utility of individualised pharmacological approaches to Ras-mediated cancer.
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Affiliation(s)
- Fiona M. Healy
- Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, United Kingdom
| | - Amy L. Turner
- Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, United Kingdom
| | - Vanessa Marensi
- Department of Biochemistry, Cell and Systems Biology, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, United Kingdom
- Chester Medical School, University of Chester, Chester, United Kingdom
| | - David J. MacEwan
- Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, United Kingdom
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Mechahougui H, Gutmans J, Colarusso G, Gouasmi R, Friedlaender A. Advances in Personalized Oncology. Cancers (Basel) 2024; 16:2862. [PMID: 39199633 PMCID: PMC11352922 DOI: 10.3390/cancers16162862] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2024] [Revised: 08/12/2024] [Accepted: 08/14/2024] [Indexed: 09/01/2024] Open
Abstract
Advances in next-generation sequencing (NGS) have catalyzed a paradigm shift in cancer treatment, steering the focus from conventional, organ-specific protocols to precision medicine. Emerging targeted therapies offer a cutting-edge approach to cancer treatment, while companion diagnostics play an essential role in aligning therapeutic choices with specific molecular changes identified through NGS. Despite these advances, interpreting the clinical implications of a rapidly expanding catalog of genetic mutations remains a challenge. The selection of therapies in the presence of multiple mutations requires careful clinical judgment, supported by quality-centric genomic testing that emphasizes actionable mutations. Molecular tumor boards can play an increasing role in assimilating genomic data into clinical trials, thereby refining personalized treatment approaches and improving patient outcomes.
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Affiliation(s)
- Hiba Mechahougui
- Oncology Department, Geneva University Hospital (HUG), 1205 Geneva, Switzerland; (H.M.)
| | - James Gutmans
- Oncology Department, Geneva University Hospital (HUG), 1205 Geneva, Switzerland; (H.M.)
| | - Gina Colarusso
- Oncology Department, Geneva University Hospital (HUG), 1205 Geneva, Switzerland; (H.M.)
| | - Roumaïssa Gouasmi
- Cancer Research Center of Lyon, CNRS UMR5286, Inserm U1052, University of Lyon, 69100 Lyon, France
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Bozzuto G, Calcabrini A, Colone M, Condello M, Dupuis ML, Pellegrini E, Stringaro A. Phytocompounds and Nanoformulations for Anticancer Therapy: A Review. Molecules 2024; 29:3784. [PMID: 39202863 PMCID: PMC11357218 DOI: 10.3390/molecules29163784] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2024] [Revised: 08/05/2024] [Accepted: 08/05/2024] [Indexed: 09/03/2024] Open
Abstract
Cancer is a complex disease that affects millions of people and remains a major public health problem worldwide. Conventional cancer treatments, including surgery, chemotherapy, immunotherapy, and radiotherapy, have limited achievements and multiple drawbacks, among which are healthy tissue damage and multidrug-resistant phenotype onset. Increasing evidence shows that many plants' natural products, as well as their bioactive compounds, have promising anticancer activity and exhibit minimal toxicity compared to conventional anticancer drugs. However, their widespread use in cancer therapy is severely restricted by limitations in terms of their water solubility, absorption, lack of stability, bioavailability, and selective targeting. The use of nanoformulations for plants' natural product transportation and delivery could be helpful in overcoming these limitations, thus enhancing their therapeutic efficacy and providing the basis for improved anticancer treatment strategies. The present review is aimed at providing an update on some phytocompounds (curcumin, resveratrol, quercetin, and cannabinoids, among others) and their main nanoformulations showing antitumor activities, both in vitro and in vivo, against such different human cancer types as breast and colorectal cancer, lymphomas, malignant melanoma, glioblastoma multiforme, and osteosarcoma. The intracellular pathways underlying phytocompound anticancer activity and the main advantages of nanoformulation employment are also examined. Finally, this review critically analyzes the research gaps and limitations causing the limited success of phytocompounds' and nanoformulations' clinical translation.
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Affiliation(s)
- Giuseppina Bozzuto
- National Center for Drug Research and Evaluation, Italian National Institute of Health, 00161 Rome, Italy; (G.B.); (M.C.); (M.C.); (M.L.D.); (A.S.)
| | - Annarica Calcabrini
- National Center for Drug Research and Evaluation, Italian National Institute of Health, 00161 Rome, Italy; (G.B.); (M.C.); (M.C.); (M.L.D.); (A.S.)
| | - Marisa Colone
- National Center for Drug Research and Evaluation, Italian National Institute of Health, 00161 Rome, Italy; (G.B.); (M.C.); (M.C.); (M.L.D.); (A.S.)
| | - Maria Condello
- National Center for Drug Research and Evaluation, Italian National Institute of Health, 00161 Rome, Italy; (G.B.); (M.C.); (M.C.); (M.L.D.); (A.S.)
| | - Maria Luisa Dupuis
- National Center for Drug Research and Evaluation, Italian National Institute of Health, 00161 Rome, Italy; (G.B.); (M.C.); (M.C.); (M.L.D.); (A.S.)
| | - Evelin Pellegrini
- Laboratory of Experimental Oncology, IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy;
| | - Annarita Stringaro
- National Center for Drug Research and Evaluation, Italian National Institute of Health, 00161 Rome, Italy; (G.B.); (M.C.); (M.C.); (M.L.D.); (A.S.)
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11
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Ghosh S, Bhuniya T, Dey A, Koley M, Roy P, Bera A, Gol D, Chowdhury A, Chowdhury R, Sen S. An Updated Review on KRAS Mutation in Lung Cancer (NSCLC) and Its Effects on Human Health. Appl Biochem Biotechnol 2024; 196:4661-4678. [PMID: 37897621 DOI: 10.1007/s12010-023-04748-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/17/2023] [Indexed: 10/30/2023]
Abstract
The largest cause of cancer-related fatalities worldwide is lung cancer. In its early stages, lung cancer often exhibits no signs or symptoms. Its signs and symptoms often appear when the condition is advanced. The Kirsten rat sarcoma virus oncogene homolog is one of the most frequently mutated oncogenes found in non-small cell lung cancer. Patients who have these mutations may do worse than those who do not, in terms of survival. To understand the nuances in order to choose the best treatment options for each patient, including combination therapy and potential resistance mechanisms, given the quick development of pharmaceuticals, it is necessary to know the factors that might contribute to this disease. It has been observed that single nucleotide polymorphisms altering let-7 micro-RNA might impact cancer propensity. On the other hand, gefitinib fails to stop the oncogenic protein from directly interacting with phosphoinositide3-kinase, which may explain its resistance towards cancer cells. Additionally, Atorvastatin may be able to overpower gefitinib resistance in these cancer cells that have this mutation regardless of the presence of phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha. De novo lipogenesis is also regulated by this virus. To overcome these effects, several targeted therapies have been proposed. One such therapy is to use inhibitors of focal adhesion kinases. When this is inhibited, viral oncogene mutant cancers are effectively stopped because it functions downstream of the virus. Mutant oncoproteins like epidermal growth factor receptor may depend on Heat Shock protein90 chaperones more frequently than they do on natural counterparts that make it more attractive therapeutic target for this virus. Inhibition of the phosphoinositide 3-kinase pathway is frequent in lung cancer, and fabrication of inhibitors against this pathway can also be an effective therapeutic strategy. Blocking programmed cell death ligand1 is another therapy that may help T cells to recognize and eliminate cancerous cells. This homolog is a challenging therapeutic target due to its complex structural makeup and myriad biological characteristics. Thanks to the unrelenting efforts of medical research, with the use of some inhibitors, immunotherapy, and other combination methods, this problem is currently expected to be overcome.
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Affiliation(s)
- Subhrojyoti Ghosh
- Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, IIT Madras, Chennai, Tamil Nadu, 600036, India.
| | - Tiyasa Bhuniya
- Department of Biotechnology, NIT Durgapur, Mahatma Gandhi Rd, A-Zone, Durgapur, West Bengal, 713209, India
| | - Anuvab Dey
- Department of Biological Sciences and Bioengineering, North Guwahati, Assam, IIT Guwahati, Assam-781039, India
| | - Madhurima Koley
- Department of Chemistry and Chemical Biology, IIT(ISM), Dhanbad, 826004, India
| | - Preeti Roy
- Department of Biotechnology, Indian Institute of Technology, Mandi, India
| | - Aishi Bera
- Department of Biotechnology, Heritage, Institute of Technology, Kolkata, West Bengal, 700107, India
| | - Debarshi Gol
- Department of Biotechnology, Heritage, Institute of Technology, Kolkata, West Bengal, 700107, India
| | - Ankita Chowdhury
- Department of Biotechnology, Heritage, Institute of Technology, Kolkata, West Bengal, 700107, India
| | - Rajanyaa Chowdhury
- Department of Biotechnology, Heritage, Institute of Technology, Kolkata, West Bengal, 700107, India
| | - Shinjini Sen
- Department of Biotechnology, Heritage, Institute of Technology, Kolkata, West Bengal, 700107, India
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Vanclooster P, Seghers S, Prenen H. State-of-the-art and upcoming trends in RAS-directed therapies in gastrointestinal malignancies. Curr Opin Oncol 2024; 36:313-319. [PMID: 38726828 DOI: 10.1097/cco.0000000000001042] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/07/2024]
Abstract
PURPOSE OF REVIEW Overall, the review underscores the evolving landscape of KRAS-targeted therapy and the potential for these approaches to improve outcomes for patients with gastrointestinal malignancies. It highlights the importance of ongoing research and clinical trials in advancing precision medicine strategies for KRAS-driven cancers. This review provides a comprehensive overview of the RAS signaling pathway and its significance in gastrointestinal malignancies. RECENT FINDINGS The introduction of KRAS inhibitor represents a significant advancement in the treatment landscape for KRAS-mutant cancers. In this review, we discuss upcoming trends in KRAS-targeted therapy, including the development of mutant-specific direct KRAS inhibitors like MRTX1133 and pan-RAS inhibitors such as RMC-6236. It also explores indirect RAS inhibitors targeting upstream and downstream components of the RAS pathway. Additionally, the review examines other upcoming strategies like combination therapies, such as CDK4/6 and ERK MAPK inhibitors, as well as adoptive cell therapy and cancer vaccines targeting KRAS-mutant cancers. SUMMARY Targeting RAS has become an important strategy in treating gastrointestinal cancer. These findings in this review underscore the importance of a multidisciplinary approach, integrating advances in molecular profiling, targeted therapy, immunotherapy, and clinical research to optimize treatment strategies for patients with KRAS-mutant gastrointestinal malignancies.
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Affiliation(s)
| | - Sofie Seghers
- Department of Oncology, Antwerp University Hospital, Edegem
- Center for Oncological Research (CORE)
| | - Hans Prenen
- Department of Oncology, Antwerp University Hospital, Edegem
- Center for Oncological Research (CORE)
- Integrated Personalized & Precision Oncology Network (IPPON), University of Antwerp, Wilrijk, Belgium
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13
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Zheng E, Włodarczyk M, Węgiel A, Osielczak A, Możdżan M, Biskup L, Grochowska A, Wołyniak M, Gajewski D, Porc M, Maryńczak K, Dziki Ł. Navigating through novelties concerning mCRC treatment-the role of immunotherapy, chemotherapy, and targeted therapy in mCRC. Front Surg 2024; 11:1398289. [PMID: 38948479 PMCID: PMC11211389 DOI: 10.3389/fsurg.2024.1398289] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2024] [Accepted: 05/29/2024] [Indexed: 07/02/2024] Open
Abstract
Over the course of nearly six decades since the inception of initial trials involving 5-FU in the treatment of mCRC (metastatic colorectal cancer), our progressive comprehension of the pathophysiology, genetics, and surgical techniques related to mCRC has paved the way for the introduction of novel therapeutic modalities. These advancements not only have augmented the overall survival but have also positively impacted the quality of life (QoL) for affected individuals. Despite the remarkable progress made in the last two decades in the development of chemotherapy, immunotherapy, and target therapies, mCRC remains an incurable disease, with a 5-year survival rate of 14%. In this comprehensive review, our primary goal is to present an overview of mCRC treatment methods following the latest guidelines provided by the National Comprehensive Cancer Network (NCCN), the American Society of Clinical Oncology (ASCO), and the American Society of Colon and Rectal Surgeons (ASCRS). Emphasis has been placed on outlining treatment approaches encompassing chemotherapy, immunotherapy, targeted therapy, and surgery's role in managing mCRC. Furthermore, our review delves into prospective avenues for developing new therapies, offering a glimpse into the future of alternative pathways that hold potential for advancing the field.
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Affiliation(s)
- Edward Zheng
- Department of General and Oncological Surgery, Faculty of Medicine, Medical University of Lodz, Lodz, Poland
| | - Marcin Włodarczyk
- Department of General and Oncological Surgery, Faculty of Medicine, Medical University of Lodz, Lodz, Poland
| | - Andrzej Węgiel
- Department of General and Oncological Surgery, Faculty of Medicine, Medical University of Lodz, Lodz, Poland
| | - Aleksandra Osielczak
- Department of General and Oncological Surgery, Faculty of Medicine, Medical University of Lodz, Lodz, Poland
| | - Maria Możdżan
- Department of General and Oncological Surgery, Faculty of Medicine, Medical University of Lodz, Lodz, Poland
| | - Laura Biskup
- Department of General and Oncological Surgery, Faculty of Medicine, Medical University of Lodz, Lodz, Poland
| | - Agata Grochowska
- Department of General and Oncological Surgery, Faculty of Medicine, Medical University of Lodz, Lodz, Poland
| | - Maria Wołyniak
- Department of General and Oncological Surgery, Faculty of Medicine, Medical University of Lodz, Lodz, Poland
- Department of Biostatistics and Translational Medicine, Medical University of Lodz, Lodz, Poland
| | - Dominik Gajewski
- Department of General and Oncological Surgery, Faculty of Medicine, Medical University of Lodz, Lodz, Poland
| | - Mateusz Porc
- Department of General and Oncological Surgery, Faculty of Medicine, Medical University of Lodz, Lodz, Poland
| | - Kasper Maryńczak
- Department of General and Oncological Surgery, Faculty of Medicine, Medical University of Lodz, Lodz, Poland
| | - Łukasz Dziki
- Department of General and Oncological Surgery, Faculty of Medicine, Medical University of Lodz, Lodz, Poland
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14
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Tonello M, Baratti D, Sammartino P, Di Giorgio A, Robella M, Sassaroli C, Framarini M, Valle M, Macrì A, Graziosi L, Coccolini F, Lippolis PV, Gelmini R, Deraco M, Biacchi D, Aulicino M, Vaira M, De Franciscis S, D'Acapito F, Carboni F, Milone E, Donini A, Fugazzola P, Faviana P, Sorrentino L, Pizzolato E, Cenzi C, Del Bianco P, Sommariva A. Prognostic value of specific KRAS mutations in patients with colorectal peritoneal metastases. ESMO Open 2024; 9:102976. [PMID: 38613907 PMCID: PMC11033065 DOI: 10.1016/j.esmoop.2024.102976] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Revised: 02/17/2024] [Accepted: 02/29/2024] [Indexed: 04/15/2024] Open
Abstract
BACKGROUND There is little evidence on KRAS mutational profiles in colorectal cancer (CRC) peritoneal metastases (PM). This study aims to determine the prevalence of specific KRAS mutations and their prognostic value in a homogeneous cohort of patients with isolated CRC PM treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. MATERIALS AND METHODS Data were collected from 13 Italian centers, gathered in a collaborative group of the Italian Society of Surgical Oncology. KRAS mutation subtypes have been correlated with clinical and pathological characteristics and survival [overall survival (OS), local (peritoneal) disease-free survival (LDFS) and disease-free survival (DFS)]. RESULTS KRAS mutations occurred in 172 patients (47.5%) out of the 362 analyzed. Two different prognostic groups of KRAS mutation subtypes were identified: KRASMUT1 (G12R, G13A, G13C, G13V, Q61H, K117N, A146V), median OS > 120 months and KRASMUT2 (G12A, G12C, G12D, G12S, G12V, G13D, A59E, A59V, A146T), OS: 31.2 months. KRASMUT2 mutations mainly occurred in the P-loop region (P < 0.001) with decreased guanosine triphosphate (GTP) hydrolysis activity (P < 0.001) and were more frequently related to size (P < 0.001) and polarity change (P < 0.001) of the substituted amino acid (AA). When KRASMUT1 and KRASMUT2 were combined with other known prognostic factors (peritoneal cancer index, completeness of cytoreduction score, grading, signet ring cell, N status) in multivariate analysis, KRASMUT1 showed a similar survival rate to KRASWT patients, whereas KRASMUT2 was independently associated with poorer prognosis (hazard ratios: OS 2.1, P < 0.001; DFS 1.9, P < 0.001; LDFS 2.5, P < 0.0001). CONCLUSIONS In patients with CRC PM, different KRAS mutation subgroups can be determined according to specific codon substitution, with some mutations (KRASMUT1) that could have a similar prognosis to wild-type patients. These findings should be further investigated in larger series.
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Affiliation(s)
- M Tonello
- Unit of Surgical Oncology of the Esophagus and Digestive Tract, Veneto Institute of Oncology IOV-IRCCS, Padua
| | - D Baratti
- Peritoneal Surface Malignancy Unit, Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan
| | - P Sammartino
- Cytoreductive Surgery and HIPEC Unit, Department of Surgery 'Pietro Valdoni', Sapienza University of Rome, Rome
| | - A Di Giorgio
- Surgical Unit of Peritoneum and Retroperitoneum, Fondazione Policlinico Universitario A. Gemelli, Rome
| | - M Robella
- Surgical Oncology Unit, Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Turin
| | - C Sassaroli
- Integrated Medical Surgical Research in Peritoneal Surface Malignancy, Abdominal Oncology Department, Istituto Nazionale per lo Studio e la Cura dei Tumori Fondazione Pascale IRCCS, Naples
| | - M Framarini
- General and Oncologic Department of Surgery, Morgagni-Pierantoni Hospital, AUSL Romagna, Forlì
| | - M Valle
- Peritoneal Tumours Unit, IRCCS, Regina Elena Cancer Institute, Rome
| | - A Macrì
- Peritoneal and Retroperitonel Surgical Unit-University Hospital 'G. Martino' Messina
| | - L Graziosi
- General and Emergency Surgery Department, University of Perugia, Santa Maria Della Misericordia Hospital, Perugia
| | - F Coccolini
- General Emergency and Trauma Surgery, Bufalini Hospital, Cesena; General Emergency and Trauma Surgery, Pisa University Hospital, Pisa
| | - P V Lippolis
- General and Peritoneal Surgery, Department of Surgery, Hospital University Pisa (AOUP), Pisa
| | - R Gelmini
- General and Oncological Surgery Unit, AOU of Modena University of Modena and Reggio Emilia
| | - M Deraco
- Peritoneal Surface Malignancy Unit, Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan
| | - D Biacchi
- Cytoreductive Surgery and HIPEC Unit, Department of Surgery 'Pietro Valdoni', Sapienza University of Rome, Rome
| | - M Aulicino
- Surgical Unit of Peritoneum and Retroperitoneum, Fondazione Policlinico Universitario A. Gemelli, Rome
| | - M Vaira
- Surgical Oncology Unit, Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Turin
| | - S De Franciscis
- Colorectal Surgical Oncology, Abdominal Oncology Department, Istituto Nazionale per lo Studio e la Cura dei Tumori Fondazione Pascale IRCCS, Naples
| | - F D'Acapito
- General and Oncologic Department of Surgery, Morgagni-Pierantoni Hospital, AUSL Romagna, Forlì
| | - F Carboni
- Peritoneal Tumours Unit, IRCCS, Regina Elena Cancer Institute, Rome
| | - E Milone
- Peritoneal and Retroperitonel Surgical Unit-University Hospital 'G. Martino' Messina
| | - A Donini
- General and Emergency Surgery Department, University of Perugia, Santa Maria Della Misericordia Hospital, Perugia
| | - P Fugazzola
- General surgery, Fondazione IRCCS Policlinico San Matteo, Pavia
| | - P Faviana
- Department of Surgical, Medical, Molecular Pathology and Critical Area, University of Pisa, Pisa
| | - L Sorrentino
- General and Oncological Surgery Unit, AOU of Modena University of Modena and Reggio Emilia
| | - E Pizzolato
- Unit of Surgical Oncology of the Esophagus and Digestive Tract, Veneto Institute of Oncology IOV-IRCCS, Padua
| | - C Cenzi
- Clinical Research Unit, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy
| | - P Del Bianco
- Clinical Research Unit, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy
| | - A Sommariva
- Unit of Surgical Oncology of the Esophagus and Digestive Tract, Veneto Institute of Oncology IOV-IRCCS, Padua.
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15
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Schietroma F, Anghelone A, Valente G, Beccia V, Caira G, Spring A, Trovato G, Di Bello A, Ceccarelli A, Chiofalo L, Perazzo S, Bensi M, Minucci A, Urbani A, Larocca LM, Basso M, Pozzo C, Salvatore L, Calegari MA, Tortora G. Focus on RAS Codon 61 Mutations in Metastatic Colorectal Cancer: A Retrospective Analysis. Cancers (Basel) 2024; 16:988. [PMID: 38473349 DOI: 10.3390/cancers16050988] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2024] [Revised: 02/23/2024] [Accepted: 02/26/2024] [Indexed: 03/14/2024] Open
Abstract
RAS mutations involving codon 61 are rare in metastatic colorectal cancer (mCRC), accounting for only 1-4%, but they have recently been identified with high frequency in the circulating tumor DNA (ctDNA) of patients with secondary resistance to anti-EGFRs. This retrospective monocentric study aimed to investigate the clinical phenotype and prognostic performance of codon 61 RAS-mutated mCRC. Fifty patients with codon 61 RAS-mutated mCRC treated at our institution between January 2013 and December 2021 were enrolled. Additional datasets of codon 61 RAS wild-type mCRCs (648 patients) were used as comparators. The endpoint for prognostic assessment was overall survival (OS). Metastatic involvement of the peritoneum or ovary was significantly more frequent in codon 61 RAS-mutated mCRC compared to codon 61 RAS wild-type (54 vs. 28.5%), non-codon 61 RAS-mutated (35.6%), BRAF V600E-mutated (25%), and RAS/BRAF wild-type (20.5%) cohorts. At a median follow up of 96.2 months, the median OS for codon 61 RAS-mutated patients was significantly shorter compared to RAS/BRAF wild-type (26.9 vs. 36.0 months, HR 0.56) patients, while no significant difference was observed compared to non-codon 61 RAS-mutated and BRAF V600E-mutated patients. We showed a negative prognostic impact and a statistically significant correlation between codon 61 RAS mutations and metastatic involvement of the peritoneum and ovary.
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Affiliation(s)
| | | | - Giustina Valente
- Medical Oncology, Università Cattolica del Sacro Cuore, 00168 Roma, Italy
| | - Viria Beccia
- Medical Oncology, Università Cattolica del Sacro Cuore, 00168 Roma, Italy
| | - Giulia Caira
- Medical Oncology, Università Cattolica del Sacro Cuore, 00168 Roma, Italy
| | - Alexia Spring
- Medical Oncology, Università Cattolica del Sacro Cuore, 00168 Roma, Italy
| | - Giovanni Trovato
- Medical Oncology, Università Cattolica del Sacro Cuore, 00168 Roma, Italy
| | - Armando Di Bello
- Medical Oncology, Università Cattolica del Sacro Cuore, 00168 Roma, Italy
| | - Anna Ceccarelli
- Medical Oncology, Università Cattolica del Sacro Cuore, 00168 Roma, Italy
| | - Laura Chiofalo
- Medical Oncology, Università Cattolica del Sacro Cuore, 00168 Roma, Italy
| | - Serena Perazzo
- Medical Oncology, Università Cattolica del Sacro Cuore, 00168 Roma, Italy
| | - Maria Bensi
- Medical Oncology, Università Cattolica del Sacro Cuore, 00168 Roma, Italy
| | - Angelo Minucci
- Departmental Unit of Molecular and Genomic Diagnostics, Genomics Core Facility, Gemelli Science and Technology Park (G-STeP), Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Roma, Italy
| | - Andrea Urbani
- Clinical Chemistry, Biochemistry and Molecular Biology Operations, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Roma, Italy
| | - Luigi Maria Larocca
- Patologia Oncoematologica, Dipartimento di Scienze della Salute della Donna, del Bambino e di Sanità Pubblica, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Roma, Italy
| | - Michele Basso
- Medical Oncology, Comprehensive Cancer Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Roma, Italy
| | - Carmelo Pozzo
- Medical Oncology, Comprehensive Cancer Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Roma, Italy
| | - Lisa Salvatore
- Medical Oncology, Università Cattolica del Sacro Cuore, 00168 Roma, Italy
- Medical Oncology, Comprehensive Cancer Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Roma, Italy
| | - Maria Alessandra Calegari
- Medical Oncology, Comprehensive Cancer Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Roma, Italy
| | - Giampaolo Tortora
- Medical Oncology, Università Cattolica del Sacro Cuore, 00168 Roma, Italy
- Medical Oncology, Comprehensive Cancer Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Roma, Italy
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16
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Zhang X, Ma H, He Y, He W, Chen N, Li Y, Zhong W, Wu G, Zhou X, Hua H, Ye F, Cai H, Jiang W. Reclassification of RAS/BRAF allele mutations predicts the survival benefit of triplet chemotherapy in metastatic colorectal cancer. Ther Adv Med Oncol 2024; 16:17588359231225035. [PMID: 38293276 PMCID: PMC10826380 DOI: 10.1177/17588359231225035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2023] [Accepted: 12/13/2023] [Indexed: 02/01/2024] Open
Abstract
Background Different RAS/BRAF allele mutations imply distinct biological properties in various solid tumors. Recently, several studies have focused on the predictive and prognostic roles of various RAS/BRAF allele mutations in colorectal cancer (CRC) but the results remain controversial. Methods Between March 2017 and September 2022, the patients diagnosed as stages I-IV CRC with detailed medical records including next-generation sequencing (NGS) data and clinicopathological follow-up information available at our center were enrolled. Survival data were estimated using the Kaplan-Meier method, and the difference was tested in a log-rank test. Multivariate tests were carried out using Cox models. Results A total of 1029 CRC patients were included, and the incidence of RAS/BRAF mutation was 58.4%. The hypermutated cohort was defined as patients with microsatellite instability-H or POLE/D mutation. In the non-hypermutational cohort, only KRAS G13D mutation was associated with a higher incidence and inferior disease-free survival in patients with stage I-III CRC. In the cohort of patients with non-hypermutated metastatic colorectal cancer (mCRC), we assessed the risk of various RAS/BRAF allele mutations and subsequently reclassified patients into four groups based on first-line median progression-free survival: wild type (group 1), low-risk RAS/BRAF mutation (group 2, RAS/BRAF mutations other than KRAS G13D/G12V/G12C or BRAF V600E), high-risk RAS mutation (group 3, KRAS G13D/G12V/G12C), and BRAF V600E mutation (group 4). mCRC patients with high-risk RAS mutation could significantly benefit from intensive triplet chemotherapy (hazard ratio, 2.54; 95% confidence interval, 1.36-5.12; p = 0.0091). Conclusion In the non-hypermutated CRC cohort, the prognostic risk of various RAS/BRAF allele mutations varied between local and metastatic CRC. KRAS G13D mutation tended to be the only prognostic marker for stages I-III CRC; however, KRAS G13D/G12V/G12C mutations collectively defined a high-risk subgroup of mCRC patients with poor prognosis, who would benefit from intensive triplet chemotherapy.
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Affiliation(s)
- Xiang Zhang
- Department of Colorectal Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- First Clinical Medical College, Lanzhou University, Lanzhou, China
- NHC Key Laboratory of Diagnosis and Therapy of Gastrointestinal Tumor, Gansu Provincial Hospital, Lanzhou, China
| | - Haizhong Ma
- NHC Key Laboratory of Diagnosis and Therapy of Gastrointestinal Tumor, Gansu Provincial Hospital, Lanzhou, China
- Key Laboratory of Molecular Diagnostics and Precision Medicine for Surgical Oncology in Gansu Province, Gansu Provincial Hospital, Gansu, China
| | - Yinjun He
- Department of Colorectal Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- College of Medicine, Zhejiang University, Hangzhou, China
| | - Wenguang He
- Department of Radiology, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Nan Chen
- Departments of Colorectal Surgery, Yuyao Hospital of Traditional Chinese Medicine, Yuyao, China
| | - Yandong Li
- Department of Colorectal Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Weixiang Zhong
- Department of Pathology, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Guosheng Wu
- Department of Colorectal Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xile Zhou
- Department of Colorectal Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Hanju Hua
- Department of Colorectal Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Feng Ye
- Department of Colorectal Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Hui Cai
- NHC Key Laboratory of Diagnosis and Therapy of Gastrointestinal Tumor, Gansu Provincial Hospital, Lanzhou 730000, China
- Key Laboratory of Molecular Diagnostics and Precision Medicine for Surgical Oncology in Gansu Province, Gansu Provincial Hospital, 204 Donggang West Road, Chengguan District, Lanzhou City, Gansu Province, China, 730000
| | - Weiqin Jiang
- Department of Colorectal Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Shangcheng District Hangzhou, Zhejiang Province China, 310003
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Bahar ME, Kim HJ, Kim DR. Targeting the RAS/RAF/MAPK pathway for cancer therapy: from mechanism to clinical studies. Signal Transduct Target Ther 2023; 8:455. [PMID: 38105263 PMCID: PMC10725898 DOI: 10.1038/s41392-023-01705-z] [Citation(s) in RCA: 203] [Impact Index Per Article: 101.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2023] [Revised: 11/03/2023] [Accepted: 11/12/2023] [Indexed: 12/19/2023] Open
Abstract
Metastatic dissemination of solid tumors, a leading cause of cancer-related mortality, underscores the urgent need for enhanced insights into the molecular and cellular mechanisms underlying metastasis, chemoresistance, and the mechanistic backgrounds of individuals whose cancers are prone to migration. The most prevalent signaling cascade governed by multi-kinase inhibitors is the mitogen-activated protein kinase (MAPK) pathway, encompassing the RAS-RAF-MAPK kinase (MEK)-extracellular signal-related kinase (ERK) pathway. RAF kinase is a primary mediator of the MAPK pathway, responsible for the sequential activation of downstream targets, such as MEK and the transcription factor ERK, which control numerous cellular and physiological processes, including organism development, cell cycle control, cell proliferation and differentiation, cell survival, and death. Defects in this signaling cascade are associated with diseases such as cancer. RAF inhibitors (RAFi) combined with MEK blockers represent an FDA-approved therapeutic strategy for numerous RAF-mutant cancers, including melanoma, non-small cell lung carcinoma, and thyroid cancer. However, the development of therapy resistance by cancer cells remains an important barrier. Autophagy, an intracellular lysosome-dependent catabolic recycling process, plays a critical role in the development of RAFi resistance in cancer. Thus, targeting RAF and autophagy could be novel treatment strategies for RAF-mutant cancers. In this review, we delve deeper into the mechanistic insights surrounding RAF kinase signaling in tumorigenesis and RAFi-resistance. Furthermore, we explore and discuss the ongoing development of next-generation RAF inhibitors with enhanced therapeutic profiles. Additionally, this review sheds light on the functional interplay between RAF-targeted therapies and autophagy in cancer.
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Affiliation(s)
- Md Entaz Bahar
- Department of Biochemistry and Convergence Medical Sciences and Institute of Medical Science, Gyeongsang National University, College of Medicine, Jinju, South Korea
| | - Hyun Joon Kim
- Department of Anatomy and Convergence Medical Sciences and Institute of Medical Science, Gyeongsang National University, College of Medicine, Jinju, South Korea
| | - Deok Ryong Kim
- Department of Biochemistry and Convergence Medical Sciences and Institute of Medical Science, Gyeongsang National University, College of Medicine, Jinju, South Korea.
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18
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Huo JT, Tuersun A, Yu SY, Zhang YC, Feng WQ, Xu ZQ, Zhao JK, Zong YP, Lu AG. Leveraging a KRAS-based signature to predict the prognosis and drug sensitivity of colon cancer and identifying SPINK4 as a new biomarker. Sci Rep 2023; 13:22230. [PMID: 38097680 PMCID: PMC10721872 DOI: 10.1038/s41598-023-48768-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2023] [Accepted: 11/30/2023] [Indexed: 12/17/2023] Open
Abstract
KRAS is one of the leading mutations reported in colon cancer. However, there are few studies on the application of KRAS related signature in predicting prognosis and drug sensitivity of colon cancer patient. We identified KRAS related differentially expressed genes (DEGs) using The Cancer Genome Atlas (TCGA) database. A signature closely related to overall survival was recognized with Kaplan-Meier survival analysis and univariate cox regression analysis. Then we validated this signature with overall expression score (OE score) algorithm using both scRNA-seq and bulk RNA-seq data. Based on this signature, we performed LASSO cox regression to establish a prognostic model, and corresponding scores were calculated. Differences in genomic alteration, immune microenvironment, drug sensitivity between high- and low-KRD score groups were investigated. A KRAS related signature composed of 80 DEGs in colon cancer were recognized, among which 19 genes were selected to construct a prognostic model. This KRAS related signature was significantly correlated with worse prognosis. Furthermore, patients who scored lower in the prognostic model presented a higher likelihood of responding to chemotherapy, targeted therapy and immunotherapy. Furthermore, among the 19 selected genes in the model, SPINK4 was identified as an independent prognostic biomarker. Further validation in vitro indicated the knockdown of SPINK4 promoted the proliferation and migration of SW48 cells. In conclusion, a novel KRAS related signature was identified and validated based on clinical and genomic information from TCGA and GEO databases. The signature was proved to regulate genomic alteration, immune microenvironment and drug sensitivity in colon cancer, and thus might serve as a predictor for individual prognosis and treatment.
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Affiliation(s)
- Jian-Ting Huo
- Department of General Surgery, Shanghai Minimally Invasive Surgery Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200020, People's Republic of China
| | - Abudumaimaitijiang Tuersun
- Department of General Surgery, Shanghai Minimally Invasive Surgery Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200020, People's Republic of China
| | - Su-Yue Yu
- Department of General Surgery, Shanghai Minimally Invasive Surgery Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200020, People's Republic of China
| | - Yu-Chen Zhang
- Department of General Surgery, Shanghai Minimally Invasive Surgery Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200020, People's Republic of China
| | - Wen-Qing Feng
- Department of General Surgery, Shanghai Minimally Invasive Surgery Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200020, People's Republic of China
| | - Zhuo-Qing Xu
- Department of General Surgery, Shanghai Minimally Invasive Surgery Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200020, People's Republic of China
| | - Jing-Kun Zhao
- Department of General Surgery, Shanghai Minimally Invasive Surgery Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200020, People's Republic of China.
| | - Ya-Ping Zong
- Department of General Surgery, Shanghai Minimally Invasive Surgery Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200020, People's Republic of China.
| | - Ai-Guo Lu
- Department of General Surgery, Shanghai Minimally Invasive Surgery Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200020, People's Republic of China.
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Cann CG, LaPelusa MB, Cimino SK, Eng C. Molecular and genetic targets within metastatic colorectal cancer and associated novel treatment advancements. Front Oncol 2023; 13:1176950. [PMID: 37409250 PMCID: PMC10319053 DOI: 10.3389/fonc.2023.1176950] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Accepted: 05/30/2023] [Indexed: 07/07/2023] Open
Abstract
Colorectal cancer results in the deaths of hundreds of thousands of patients worldwide each year, with incidence expected to rise over the next two decades. In the metastatic setting, cytotoxic therapy options remain limited, which is reflected in the meager improvement of patient survival rates. Therefore, focus has turned to the identification of the mutational composition inherent to colorectal cancers and development of therapeutic targeted agents. Herein, we review the most up to date systemic treatment strategies for metastatic colorectal cancer based on the actionable molecular alterations and genetic profiles of colorectal malignancies.
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Affiliation(s)
- Christopher G. Cann
- Department of Medicine: Hematology/Oncology, Vanderbilt University Medical Center, Nashville, TN, United States
| | - Michael B. LaPelusa
- Department of Medicine: Hematology/Oncology, Vanderbilt University Medical Center, Nashville, TN, United States
| | - Sarah K. Cimino
- Department of Pharmacy, Vanderbilt University Medical Center, Nashville, TN, United States
| | - Cathy Eng
- Department of Medicine: Hematology/Oncology, Vanderbilt University Medical Center, Nashville, TN, United States
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20
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Perez-Mayoral J, Gonzalez-Pons M, Centeno-Girona H, Montes-Rodríguez IM, Soto-Salgado M, Suárez B, Rodríguez N, Colón G, Sevilla J, Jorge D, Llor X, Xicola RM, Toro DH, Tous-López L, Torres-Torres M, Reyes JS, López-Acevedo N, Goel A, Rodríguez-Quilichini S, Cruz-Correa M. Molecular and Sociodemographic Colorectal Cancer Disparities in Latinos Living in Puerto Rico. Genes (Basel) 2023; 14:894. [PMID: 37107652 PMCID: PMC10138302 DOI: 10.3390/genes14040894] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Revised: 04/05/2023] [Accepted: 04/07/2023] [Indexed: 04/29/2023] Open
Abstract
BACKGROUND The incidence of sporadic colorectal cancer (CRC) among individuals <50 years (early-onset CRC) has been increasing in the United States (U.S.) and Puerto Rico. CRC is currently the leading cause of cancer death among Hispanic men and women living in Puerto Rico (PRH). The objective of this study was to characterize the molecular markers and clinicopathologic features of colorectal tumors from PRH to better understand the molecular pathways leading to CRC in this Hispanic subpopulation. METHODS Microsatellite instability (MSI), CpG island methylator phenotype (CIMP), and KRAS and BRAF mutation status were analyzed. Sociodemographic and clinicopathological characteristics were evaluated using Chi-squared and Fisher's exact tests. RESULTS Of the 718 tumors analyzed, 34.2% (n = 245) were early-onset CRC, and 51.7% were males. Among the tumors with molecular data available (n = 192), 3.2% had MSI, 9.7% had BRAF, and 31.9% had KRAS mutations. The most common KRAS mutations observed were G12D (26.6%) and G13D (20.0%); G12C was present in 4.4% of tumors. A higher percentage of Amerindian admixture was significantly associated with early-onset CRC. CONCLUSIONS The differences observed in the prevalence of the molecular markers among PRH tumors compared to other racial/ethnic groups suggest a distinct molecular carcinogenic pathway among Hispanics. Additional studies are warranted.
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Affiliation(s)
| | - Maria Gonzalez-Pons
- University of Puerto Rico Comprehensive Cancer Center, San Juan, PR 00936, USA
| | | | | | | | - Belisa Suárez
- University of Puerto Rico Comprehensive Cancer Center, San Juan, PR 00936, USA
| | - Natalia Rodríguez
- School of Medicine, Universidad Central del Caribe, Bayamon, PR 00956, USA
| | - Giancarlo Colón
- School of Medicine, Universidad Central del Caribe, Bayamon, PR 00956, USA
| | - Javier Sevilla
- School of Medicine, Universidad Central del Caribe, Bayamon, PR 00956, USA
| | - Daphne Jorge
- School of Medicine, Ponce Health Sciences University, Ponce, PR 00716, USA
| | - Xavier Llor
- Department of Internal Medicine and Digestive Diseases, School of Medicine, Yale University, New Haven, CT 06520, USA
| | - Rosa M. Xicola
- Department of Internal Medicine and Digestive Diseases, School of Medicine, Yale University, New Haven, CT 06520, USA
| | - Doris H. Toro
- VA Caribbean Healthcare System, San Juan, PR 00921, USA
| | - Luis Tous-López
- Ashford Presbyterian Community Hospital, San Juan, PR 00907, USA
| | | | - José S. Reyes
- Ashford Presbyterian Community Hospital, San Juan, PR 00907, USA
| | | | - Ajay Goel
- Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA
| | | | - Marcia Cruz-Correa
- University of Puerto Rico Comprehensive Cancer Center, San Juan, PR 00936, USA
- Department of Medicine, Medical Sciences Campus, University of Puerto Rico, San Juan, PR 00935, USA
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21
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Mesti T, Rebersek M, Ocvirk J. The five-year KRAS, NRAS and BRAF analysis results and treatment patterns in daily clinical practice in Slovenia in 1 st line treatment of metastatic colorectal (mCRC) patients with RAS wild-type tumour (wt RAS) - a real- life data report 2013-2018. Radiol Oncol 2023; 57:103-110. [PMID: 36942906 PMCID: PMC10039470 DOI: 10.2478/raon-2023-0014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Accepted: 09/30/2022] [Indexed: 03/23/2023] Open
Abstract
BACKGROUND We preformed a Phase IV non-interventional study to assess KRAS, NRAS and BRAF status in metastatic colorectal cancer (mCRC) patients suitable for 1st line treatment and to evaluate the decisions for 1st line treatment considering the treatment goals in the RAS wild type (wt) patients. The aim of our study was also to evaluate the influence of a waiting period for biomarkers analysis on the start of first-line treatment. PATIENTS AND METHODS Patients with histologically confirmed mCRC adenocarcinoma suitable for first-line treatment fulfilling all inclusion criteria were included in the study. The KRAS, NRAS and BRAF analysis was performed from tissue samples of primary tumor site or metastatic site. All included patients have given consent to participate in the study by signing the informed consent form. RESULTS From April 2013 to March 2018 at the Institute of Oncology Ljubljana 650 patients were included, 637 of them were treated with first- line systemic treatment according to RAS and BRAF status. Remaining 13 patients with mCRC did not receive systemic first-line treatment. The distribution of patients with KRAS mutated and wild-type tumors, was almost equal, 48.8% and 47.9% respectively, 89 % of the patients had wt NRAS tumours and 86.1% had wt BRAF tumours. The most frequently prescribed treatment was bevacizumab-based therapy (53.1%), either in combination with doublet chemotherapy or with mono-chemotherapy. EGFR inhibitors cetuximab and panitumumab were prescribed in wt RAS mCRC patients (30.9%). The waiting period for biomarkers analysis was two weeks. CONCLUSIONS Our real-world data, single centre 5-year analysis showed that the distribution between wild type and mutated type tumors of the patients with mCRC was approximately the same, as worldwide, so the Slovenian population with mCRC has the same ratio distribution of KRAS, NRAS and BRAF wild and mutated genes. We concluded that a two-week waiting period for biomarkers analysis did not influence the first line treatment decision, so it was in the accordance with the worldwide treatment guidelines based on evidence-based medicine.
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Affiliation(s)
- Tanja Mesti
- Department of Medical Oncology, Institute of Oncology Ljubljana, Ljubljana, Slovenia
- Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Martina Rebersek
- Department of Medical Oncology, Institute of Oncology Ljubljana, Ljubljana, Slovenia
- Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Janja Ocvirk
- Department of Medical Oncology, Institute of Oncology Ljubljana, Ljubljana, Slovenia
- Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
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22
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Current Targeted Therapy for Metastatic Colorectal Cancer. Int J Mol Sci 2023; 24:ijms24021702. [PMID: 36675216 PMCID: PMC9864602 DOI: 10.3390/ijms24021702] [Citation(s) in RCA: 60] [Impact Index Per Article: 30.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Revised: 01/07/2023] [Accepted: 01/13/2023] [Indexed: 01/17/2023] Open
Abstract
Colorectal cancer (CRC) is the third most common type of cancer and the second leading cause of cancer deaths worldwide. Surgery or surgery plus radiotherapy and/or chemotherapy for patients with metastatic CRC (mCRC) were accepted as the main therapeutic strategies until the early 2000s, when targeted drugs, like cetuximab and bevacizumab, were developed. The use of targeted drugs in clinical practice has significantly increased patients' overall survival. To date, the emergence of several types of targeted drugs has opened new possibilities and revealed new prospects for mCRC treatment. Therapeutic strategies are continually being updated to select the most suitable targeted drugs based on the results of clinical trials that are currently underway. This review discusses the up-to date molecular evidence of targeted therapy for mCRC and summarizes the Food and Drug Administration-approved targeted drugs including the results of clinical trials. We also explain their mechanisms of action and how these affect the choice of a suitable targeted therapy.
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23
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Yang H, Zhou X, Fu D, Le C, Wang J, Zhou Q, Liu X, Yuan Y, Ding K, Xiao Q. Targeting RAS mutants in malignancies: successes, failures, and reasons for hope. Cancer Commun (Lond) 2023; 43:42-74. [PMID: 36316602 PMCID: PMC9859734 DOI: 10.1002/cac2.12377] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Revised: 07/15/2022] [Accepted: 10/13/2022] [Indexed: 01/22/2023] Open
Abstract
RAS genes are the most frequently mutated oncogenes and play critical roles in the development and progression of malignancies. The mutation, isoform (KRAS, HRAS, and NRAS), position, and type of substitution vary depending on the tissue types. Despite decades of developing RAS-targeted therapies, only small subsets of these inhibitors are clinically effective, such as the allele-specific inhibitors against KRASG12C . Targeting the remaining RAS mutants would require further experimental elucidation of RAS signal transduction, RAS-altered metabolism, and the associated immune microenvironment. This study reviews the mechanisms and efficacy of novel targeted therapies for different RAS mutants, including KRAS allele-specific inhibitors, combination therapies, immunotherapies, and metabolism-associated therapies.
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Affiliation(s)
- Hang Yang
- Department of Colorectal Surgery and OncologyKey Laboratory of Cancer Prevention and InterventionMinistry of EducationThe Second Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiang310009P. R. China
| | - Xinyi Zhou
- Department of Colorectal Surgery and OncologyKey Laboratory of Cancer Prevention and InterventionMinistry of EducationThe Second Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiang310009P. R. China
| | - Dongliang Fu
- Department of Colorectal Surgery and OncologyKey Laboratory of Cancer Prevention and InterventionMinistry of EducationThe Second Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiang310009P. R. China
| | - Chenqin Le
- Department of Colorectal Surgery and OncologyKey Laboratory of Cancer Prevention and InterventionMinistry of EducationThe Second Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiang310009P. R. China
| | - Jiafeng Wang
- Department of Pharmacology and Department of Gastroenterology of the Second Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiang310058P. R. China
| | - Quan Zhou
- Department of Cell BiologySchool of Basic Medical SciencesZhejiang UniversityHangzhouZhejiang310058P. R. China
| | - Xiangrui Liu
- Department of Pharmacology and Department of Gastroenterology of the Second Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiang310058P. R. China
- Cancer CenterZhejiang UniversityHangzhouZhejiang310058P. R. China
| | - Ying Yuan
- Department of Medical Oncologythe Second Affiliated Hospital of Zhejiang University School of MedicineHangzhouZhejiang310058P. R. China
| | - Kefeng Ding
- Department of Colorectal Surgery and OncologyKey Laboratory of Cancer Prevention and InterventionMinistry of EducationThe Second Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiang310009P. R. China
- Cancer CenterZhejiang UniversityHangzhouZhejiang310058P. R. China
| | - Qian Xiao
- Department of Colorectal Surgery and OncologyKey Laboratory of Cancer Prevention and InterventionMinistry of EducationThe Second Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiang310009P. R. China
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24
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Toropovskiy AN, Nikitin AG, Viktorov DA, Solov'ev AV, Khuzina RM, Pavlova ON. The role of KRAS and NRAS mutation detection in determining the therapy strategy for colorectal cancer. BULLETIN OF THE MEDICAL INSTITUTE "REAVIZ" (REHABILITATION, DOCTOR AND HEALTH) 2022. [DOI: 10.20340/vmi-rvz.2022.5.clin.8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Colorectal cancer is one of the most frequently diagnosed malignant tumors in men and women, which is a highly heterogeneous group of neoplasms consisting of subclasses with different molecular and clinical characteristics, and, as a consequence, patients with different types of tumors require different treatment protocols. Among the predictive factors of treatment response in patients with metastatic colorectal cancer, the most studied are the genes of the RAS family (KRAS, NRAS). Determination of RAS status is the first step in individual selection of drug therapy in patients with metastatic colorectal cancer. Patients with certain mutations in KRAS and NRAS genes are resistant to anti-EGFR therapy and have a lower median survival than WT (wild type) genotypes, indicating a negative prognosis in the presence of mutations.
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Kok V, Tang JY, Eng G, Tan SY, Chin J, Quek C, Lai WX, Lim TK, Lin Q, Chua J, Cheong J. SFPQ promotes RAS-mutant cancer cell growth by modulating 5'-UTR mediated translational control of CK1α. NAR Cancer 2022; 4:zcac027. [PMID: 36177382 PMCID: PMC9513841 DOI: 10.1093/narcan/zcac027] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Revised: 08/31/2022] [Accepted: 09/07/2022] [Indexed: 11/12/2022] Open
Abstract
Oncogenic mutations in the RAS family of small GTPases are commonly found in human cancers and they promote tumorigenesis by altering gene expression networks. We previously demonstrated that Casein Kinase 1α (CK1α), a member of the CK1 family of serine/threonine kinases, is post-transcriptionally upregulated by oncogenic RAS signaling. Here, we report that the CK1α mRNA contains an exceptionally long 5'-untranslated region (UTR) harbouring several translational control elements, implicating its involvement in translational regulation. We demonstrate that the CK1α 5'-UTR functions as an IRES element in HCT-116 colon cancer cells to promote cap-independent translation. Using tobramycin-affinity RNA-pulldown assays coupled with identification via mass spectrometry, we identified several CK1α 5'-UTR-binding proteins, including SFPQ. We show that RNA interference targeting SFPQ reduced CK1α protein abundance and partially blocked RAS-mutant colon cancer cell growth. Importantly, transcript and protein levels of SFPQ and other CK1α 5'-UTR-associated RNA-binding proteins (RBPs) are found to be elevated in early stages of RAS-mutant cancers, including colorectal and lung adenocarcinoma. Taken together, our study uncovers a previously unappreciated role of RBPs in promoting RAS-mutant cancer cell growth and their potential to serve as promising biomarkers as well as tractable therapeutic targets in cancers driven by oncogenic RAS.
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Affiliation(s)
- Venetia Jing Tong Kok
- Precision Medicine Translational Research Programme, Yong Loo Lin School of Medicine (YLLSoM), National University of Singapore, Singapore
| | - Jia Ying Tang
- Precision Medicine Translational Research Programme, Yong Loo Lin School of Medicine (YLLSoM), National University of Singapore, Singapore
| | - Gracie Wee Ling Eng
- Precision Medicine Translational Research Programme, Yong Loo Lin School of Medicine (YLLSoM), National University of Singapore, Singapore
| | - Shin Yi Tan
- Precision Medicine Translational Research Programme, Yong Loo Lin School of Medicine (YLLSoM), National University of Singapore, Singapore
| | - Joseph Tin Foong Chin
- Precision Medicine Translational Research Programme, Yong Loo Lin School of Medicine (YLLSoM), National University of Singapore, Singapore
| | - Chun Hian Quek
- School of Applied Science, Temasek Polytechnic, Singapore
| | - Wei Xuan Lai
- Department of Physiology, YLLSoM, National University of Singapore, Singapore
| | - Teck Kwang Lim
- Department of Biological Sciences, Faculty of Science, National University of Singapore, Singapore
| | - Qingsong Lin
- Department of Biological Sciences, Faculty of Science, National University of Singapore, Singapore
| | - John Jia En Chua
- Department of Physiology, YLLSoM, National University of Singapore, Singapore
- LSI Neurobiology Programme, National University of Singapore, Singapore
- Healthy Longevity Translational Research Programme, YLLSoM, National University of Singapore, Singapore
| | - Jit Kong Cheong
- Precision Medicine Translational Research Programme, Yong Loo Lin School of Medicine (YLLSoM), National University of Singapore, Singapore
- NUS Centre for Cancer Research, National University of Singapore, Singapore
- Department of Biochemistry, YLLSoM, National University of Singapore, Singapore
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26
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Jethwa KR, Jin Z, Hallemeier CL. A Critical Review of the Role of Local Therapy for Oligometastatic Gastrointestinal Cancer. Int J Radiat Oncol Biol Phys 2022; 114:780-791. [DOI: 10.1016/j.ijrobp.2022.06.084] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Revised: 05/20/2022] [Accepted: 06/22/2022] [Indexed: 10/31/2022]
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Bottom-Up Approach to the Discovery of Clinically Relevant Biomarker Genes: The Case of Colorectal Cancer. Cancers (Basel) 2022; 14:cancers14112654. [PMID: 35681633 PMCID: PMC9179423 DOI: 10.3390/cancers14112654] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Revised: 05/26/2022] [Accepted: 05/26/2022] [Indexed: 12/07/2022] Open
Abstract
Traditional approaches to genome-wide marker discovery often follow a common top-down strategy, where a large scale ‘omics’ investigation is followed by the analysis of functional pathways involved, to narrow down the list of identified putative biomarkers, and to deconvolute gene expression networks, or to obtain an insight into genetic alterations observed in cancer. We set out to investigate whether a reverse approach would allow full or partial reconstruction of the transcriptional programs and biological pathways specific to a given cancer and whether the full or substantially expanded list of putative markers could thus be identified by starting with the partial knowledge of a few disease-specific markers. To this end, we used 10 well-documented differentially expressed markers of colorectal cancer (CRC), analyzed their transcription factor networks and biological pathways, and predicted the existence of 193 new putative markers. Incredibly, the use of a validation marker set of 10 other completely different known CRC markers and the same procedure resulted in a very similar set of 143 predicted markers. Of these, 138 were identical to those found using the training set, confirming our main hypothesis that a much-expanded set of disease markers can be predicted by starting with just a small subset of validated markers. Further to this, we validated the expression of 42 out of 138 top-ranked predicted markers experimentally using qPCR in surgically removed CRC tissues. We showed that 41 out of 42 mRNAs tested have significantly altered levels of mRNA expression in surgically excised CRC tissues. Of the markers tested, 36 have been reported to be associated with aspects of CRC in the past, whilst only limited published evidence exists for another three genes (BCL2, PDGFRB and TSC2), and no published evidence directly linking genes to CRC was found for CCNA1, SHC1 and TGFB3. Whilst we used CRC to test and validate our marker discovery strategy, the reported procedures apply more generally to cancer marker discovery.
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28
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Ricciuti B, Son J, Okoro JJ, Mira A, Patrucco E, Eum Y, Wang X, Paranal R, Wang H, Lin M, Haikala HM, Li J, Xu Y, Alessi JV, Chhoeu C, Redig AJ, Köhler J, Dholakia KH, Chen Y, Richard E, Nokin MJ, Santamaria D, Gokhale PC, Awad MM, Jänne PA, Ambrogio C. Comparative Analysis and Isoform-Specific Therapeutic Vulnerabilities of KRAS Mutations in Non-Small Cell Lung Cancer. Clin Cancer Res 2022; 28:1640-1650. [PMID: 35091439 PMCID: PMC10979418 DOI: 10.1158/1078-0432.ccr-21-2719] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2021] [Revised: 12/21/2021] [Accepted: 01/25/2022] [Indexed: 11/16/2022]
Abstract
PURPOSE Activating missense mutations of KRAS are the most frequent oncogenic driver events in lung adenocarcinoma (LUAD). However, KRAS isoforms are highly heterogeneous, and data on the potential isoform-dependent therapeutic vulnerabilities are still lacking. EXPERIMENTAL DESIGN We developed an isogenic cell-based platform to compare the oncogenic properties and specific therapeutic actionability of KRAS-mutant isoforms. In parallel, we analyzed clinicopathologic and genomic data from 3,560 patients with non-small cell lung cancer (NSCLC) to survey allele-specific features associated with oncogenic KRAS mutations. RESULTS In isogenic cell lines expressing different mutant KRAS isoforms, we identified isoform-specific biochemical, biological, and oncogenic properties both in vitro and in vivo. These exclusive features correlated with different therapeutic responses to MEK inhibitors, with KRAS G12C and Q61H mutants being more sensitive compared with other isoforms. In vivo, combined KRAS G12C and MEK inhibition was more effective than either drug alone. Among patients with NSCLCs that underwent comprehensive tumor genomic profiling, STK11 and ATM mutations were significantly enriched among tumors harboring KRAS G12C, G12A, and G12V mutations. KEAP1 mutation was significantly enriched among KRAS G12C and KRAS G13X LUADs. KRAS G13X-mutated tumors had the highest frequency of concurrent STK11 and KEAP1 mutations. Transcriptomic profiling revealed unique patterns of gene expression in each KRAS isoform, compared with KRAS wild-type tumors. CONCLUSIONS This study demonstrates that KRAS isoforms are highly heterogeneous in terms of concurrent genomic alterations and gene-expression profiles, and that stratification based on KRAS alleles should be considered in the design of future clinical trials.
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Affiliation(s)
- Biagio Ricciuti
- Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, USA
| | - Jieun Son
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, USA
| | - Jeffrey J. Okoro
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, USA
| | - Alessia Mira
- Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Torino, Torino, Italy
| | - Enrico Patrucco
- Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Torino, Torino, Italy
| | - Yoonji Eum
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, USA
| | - Xinan Wang
- Harvard Graduate School of Arts and Sciences, Harvard University, Cambridge, USA
- Department of Environmental Health, Harvard T.H. Chan School of Public Health, Harvard University, Boston, USA
| | - Raymond Paranal
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, USA
| | - Haiyun Wang
- School of Life Sciences and Technology, Tongji University, Shanghai 200092, China
| | - Mika Lin
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, USA
| | - Heidi M. Haikala
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, USA
| | - Jiaqi Li
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, USA
| | - Yue Xu
- School of Life Sciences and Technology, Tongji University, Shanghai 200092, China
| | - Joao Victor Alessi
- Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, USA
| | - Chhayheng Chhoeu
- Experimental Therapeutics Core and Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, USA
| | - Amanda J. Redig
- Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, USA
| | - Jens Köhler
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, USA
| | - Kshiti H. Dholakia
- Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, USA
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, USA
| | - Yunhan Chen
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, USA
| | - Elodie Richard
- Institut Bergonié, INSERM U1218, ACTION Laboratory, Bordeaux, France
| | - Marie-Julie Nokin
- University of Bordeaux, INSERM U1218, ACTION Laboratory, IECB, Pessac, France
| | - David Santamaria
- University of Bordeaux, INSERM U1218, ACTION Laboratory, IECB, Pessac, France
| | - Prafulla C. Gokhale
- Experimental Therapeutics Core and Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, USA
| | - Mark M. Awad
- Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, USA
| | - Pasi A. Jänne
- Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, USA
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, USA
| | - Chiara Ambrogio
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, USA
- Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Torino, Torino, Italy
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Colorectal Cancer Diagnosis: The Obstacles We Face in Determining a Non-Invasive Test and Current Advances in Biomarker Detection. Cancers (Basel) 2022; 14:cancers14081889. [PMID: 35454792 PMCID: PMC9029324 DOI: 10.3390/cancers14081889] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Revised: 04/04/2022] [Accepted: 04/06/2022] [Indexed: 02/07/2023] Open
Abstract
Simple Summary Colorectal cancer (CRC) is one of the most common cancers in the western world. CRC originates from precursor adenomatous polyps, which may over time develop into cancer. Endoscopic evaluation remains the gold-standard investigation for the disease. In the absence of molecular tools for early detection, the removal of neoplastic adenomas via polypectomy remains an important measure to prevent dysplastic adenomas from evolving into invasive carcinoma. Colonoscopy is an intrusive procedure that provides an uncomfortable experience for patients. Kits for testing for the presence of blood hemoglobin in the stool are now widely used, and DNA methylation-based detection kits have been approved in the USA for testing the stool and plasma, but few other molecular biomarkers have found their way into medical practice. This review summarizes current trends in the detection and screening of CRC and provides a definitive review of emerging molecular biomarkers for CRC. Abstract Globally, colorectal cancer (CRC) is the third most common cancer, with 1.4 million new cases and over 700,000 deaths per annum. Despite being one of the most common cancers, few molecular approaches to detect CRC exist. Carcinoembryonic antigen (CEA) is a known serum biomarker that is used in CRC for monitoring disease recurrence or response to treatment. However, it can also be raised in multiple benign conditions, thus having no value in early detection or screening for CRC. Molecular biomarkers play an ever-increasing role in the diagnosis, prognosis, and outcome prediction of disease, however, only a limited number of biomarkers are available and none are suitable for early detection and screening of CRC. A PCR-based Epi proColon® blood plasma test for the detection of methylated SEPT9 has been approved by the USFDA for CRC screening in the USA, alongside a stool test for methylated DNA from CRC cells. However, these are reserved for patients who decline traditional screening methods. There remains an urgent need for the development of non-invasive molecular biomarkers that are highly specific and sensitive to CRC and that can be used routinely for early detection and screening. A molecular approach to the discovery of CRC biomarkers focuses on the analysis of the transcriptome of cancer cells to identify differentially expressed genes and proteins. A systematic search of the literature yielded over 100 differentially expressed CRC molecular markers, of which the vast majority are overexpressed in CRC. In terms of function, they largely belong to biological pathways involved in cell division, regulation of gene expression, or cell proliferation, to name a few. This review evaluates the current methods used for CRC screening, current availability of biomarkers, and new advances within the field of biomarker detection for screening and early diagnosis of CRC.
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Proudman D, DeVito NC, Belinson S, Allo MA, Morris ED, Signorovitch J, Patel AK. Comprehensive genomic profiling in advanced/metastatic colorectal cancer: number needed to test and budget impact of expanded first line use. J Med Econ 2022; 25:817-825. [PMID: 35593483 DOI: 10.1080/13696998.2022.2080463] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
AIMS Use of comprehensive genomic profiling (CGP) in metastatic colorectal cancer (mCRC) is limited. We estimated impacts of expanded 1 L CGP, using the Tempus xT test, on detection of actionable alterations and testing budgets in a modeled US health plan over two-years. MATERIALS AND METHODS A decision analytic model was developed to estimate the impact of replacing 20% of usual testing (a mix of CGP and non-CGP) with Tempus xT CGP. Actionable alterations for matched treatments or clinical trial included KRAS, NRAS, RAF, BRAF, deficient mismatch repair (dMMR)/microsatellite instability (MSI), NTRK, RET, EGFR, HER2, MET, PIK3CA and POLE1. Costs included initial and repeat testing, physician-associated and administrative costs. RESULTS In a hypothetical five-million-member plan, 50% Medicare and 50% commercial, 1,112 new cases of mCRC were expected per year. Of these, 566 (51%) would undergo 1 L molecular testing, with 55 re-tested upon progression. Based on current testing rates, there were an expected 521 missed opportunities for genomically informed treatment (47% of new cases), with 442 missed due to lack of testing and 79 due to testing without CGP. Replacing 20% of usual testing with Tempus xT CGP was associated with up to a $0.003 per member per month testing cost increase (net total cost of $202,102 for the five-million-member plan) and 15.5 additional patients with an opportunity for genomically informed care (12.7 patients for treatment and 2.8 for clinical trial). The testing total cost (initial test, repeat test, biopsy and physician services, and administrative cost) to put one additional patient with mCRC on matched therapy or matched clinical trial was estimated to be $13,005. Number needed to test to identify one actionable alteration with Tempus xT CGP versus usual testing was 7.8 patients. LIMITATIONS Conservative assumptions were made for inputs with limited evidence. Based on high concordance rates with dMMR/MSI status, tumor mutational burden (TMB) status was not calculated separately. CONCLUSIONS Replacing 20% of usual testing with Tempus xT CGP was associated with a small incremental testing cost and can identify meaningfully more actionable alterations.
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Fan G, Lou L, Song Z, Zhang X, Xiong XF. Targeting mutated GTPase KRAS in tumor therapies. Eur J Med Chem 2021; 226:113816. [PMID: 34520956 DOI: 10.1016/j.ejmech.2021.113816] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Revised: 08/24/2021] [Accepted: 08/29/2021] [Indexed: 12/13/2022]
Abstract
Kirsten rat sarcoma virus oncogene (KRAS) mutation accounts for approximately 85% of RAS-driven cancers, and participates in multiple signaling pathways and mediates cell proliferation, differentiation and metabolism. KRAS has been considered as an "undruggable" target due to the lack of effective direct inhibitors, although high frequency of KRAS mutations have been identified in multiple carcinomas in the past decades. Encouragingly, the KRASG12C inhibitor AMG510 (sotorasib), which has been approved for treating NSCLC and CRC recently, makes directly targeting KRAS the most promising strategy for cancer therapy. To better understand the current state of KRAS inhibitors, this review summarizes the biological functions of KRAS, the structure-activity relationship studies of the small-molecule inhibitors that directly target KRAS, and highlights the therapeutic agents with improved selectivity, bioavailability and physicochemical properties. Furthermore, the combined medication that can enhance efficacy and overcome drug resistance of KRAS covalent inhibitors is also reviewed.
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Affiliation(s)
- Guangjin Fan
- Guangdong Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, 510006, China
| | - Linlin Lou
- Guangdong Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, 510006, China
| | - Zhendong Song
- Guangdong Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, 510006, China.
| | - Xiaolei Zhang
- Guangdong Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, 510006, China.
| | - Xiao-Feng Xiong
- Guangdong Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, 510006, China.
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Promsorn J, Chadbunchachai P, Somsap K, Paonariang K, Sa-ngaimwibool P, Apivatanasiri C, Lahoud RM, Harisinghani M. Imaging features associated with survival outcomes among colorectal cancer patients with and without KRAS mutation. THE EGYPTIAN JOURNAL OF RADIOLOGY AND NUCLEAR MEDICINE 2021. [DOI: 10.1186/s43055-020-00393-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Abstract
Background
Mutations in Kirsten rat sarcoma proto-oncogene (KRAS) have been shown to be associated with advanced-stage colorectal cancer (CRC), negative disease outcomes, and poor response to treatment. The purpose of this study was to investigate which CT features are biomarkers for KRAS gene mutation and impact the survival outcomes of colorectal cancer patients.
Results
Of the 113 CRC patients included in the study, 46 had KRAS mutations (40.71%) and 67 had no mutations (59.29%). Regional lymph node necrosis was the only imaging feature significantly associated with KRAS mutation (P = 0.011). Higher T staging and liver, lung, and distant metastasis were prognostic factors for CRC (P = 0.014, P < 0.001, P = 0.022, P < 0.001, respectively). There were no significant differences in overall survival between patients with KRAS mutations and those without (P = 0.159). However, in patients with no KRAS mutation, those with CRC on the left side had a significantly higher rate of survival than those with CRC on the right (P = 0.005).
Conclusion
Regional lymph node necrosis may be an imaging biomarker of CRC with KRAS mutation, possibly indicating poor prognosis.
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van 't Erve I, Wesdorp NJ, Medina JE, Ferreira L, Leal A, Huiskens J, Bolhuis K, van Waesberghe JHTM, Swijnenburg RJ, van den Broek D, Velculescu VE, Kazemier G, Punt CJA, Meijer GA, Fijneman RJA. KRAS A146 Mutations Are Associated With Distinct Clinical Behavior in Patients With Colorectal Liver Metastases. JCO Precis Oncol 2021; 5:PO.21.00223. [PMID: 34820593 PMCID: PMC8608264 DOI: 10.1200/po.21.00223] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2021] [Revised: 08/23/2021] [Accepted: 10/13/2021] [Indexed: 12/11/2022] Open
Abstract
Somatic KRAS mutations occur in approximately half of the patients with metastatic colorectal cancer (mCRC). Biologic tumor characteristics differ on the basis of the KRAS mutation variant. KRAS mutations are known to influence patient prognosis and are used as predictive biomarker for treatment decisions. This study examined clinical features of patients with mCRC with a somatic mutation in KRAS G12, G13, Q61, K117, or A146. Patients with mCRC and a KRAS A146 mutation are characterized by high tumor burden and poor prognosis![]()
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Affiliation(s)
- Iris van 't Erve
- Department of Pathology, The Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - Nina J Wesdorp
- Deparment of Surgery, Cancer Center Amsterdam, Amsterdam University Medical Centers, VU University, Amsterdam, the Netherlands
| | - Jamie E Medina
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Leonardo Ferreira
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Alessandro Leal
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD.,Center for Personalized Medicine, Hospital Israelita Albert Einstein, São Paulo, Brazil
| | | | - Karen Bolhuis
- Department of Medical Oncology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands
| | - Jan-Hein T M van Waesberghe
- Deparment of Radiology and Molecular Imaging, Cancer Center Amsterdam, Amsterdam University Medical Centers, VU University, Amsterdam, the Netherlands
| | - Rutger-Jan Swijnenburg
- Deparment of Surgery, Cancer Center Amsterdam, Amsterdam University Medical Centers, VU University, Amsterdam, the Netherlands
| | - Daan van den Broek
- Department for Laboratory Medicine, The Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - Victor E Velculescu
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Geert Kazemier
- Deparment of Surgery, Cancer Center Amsterdam, Amsterdam University Medical Centers, VU University, Amsterdam, the Netherlands
| | - Cornelis J A Punt
- Department of Medical Oncology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands.,Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Gerrit A Meijer
- Department of Pathology, The Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - Remond J A Fijneman
- Department of Pathology, The Netherlands Cancer Institute, Amsterdam, the Netherlands
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Role of oncogenic KRAS in the prognosis, diagnosis and treatment of colorectal cancer. Mol Cancer 2021; 20:143. [PMID: 34742312 PMCID: PMC8571891 DOI: 10.1186/s12943-021-01441-4] [Citation(s) in RCA: 221] [Impact Index Per Article: 55.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Accepted: 10/04/2021] [Indexed: 02/08/2023] Open
Abstract
Colorectal cancer (CRC) is a heterogeneous disease at the cellular and molecular levels. Kirsten rat sarcoma (KRAS) is a commonly mutated oncogene in CRC, with mutations in approximately 40% of all CRC cases; its mutations result in constitutive activation of the KRAS protein, which acts as a molecular switch to persistently stimulate downstream signaling pathways, including cell proliferation and survival, thereby leading to tumorigenesis. Patients whose CRC harbors KRAS mutations have a dismal prognosis. Currently, KRAS mutation testing is a routine clinical practice before treating metastatic cases, and the approaches developed to detect KRAS mutations have exhibited favorable sensitivity and accuracy. Due to the presence of KRAS mutations, this group of CRC patients requires more precise therapies. However, KRAS was historically thought to be an undruggable target until the development of KRASG12C allele-specific inhibitors. These promising inhibitors may provide novel strategies to treat KRAS-mutant CRC. Here, we provide an overview of the role of KRAS in the prognosis, diagnosis and treatment of CRC.
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Yamamoto S, Nagashima K, Kawakami T, Mitani S, Komoda M, Tsuji Y, Izawa N, Kawakami K, Yamamoto Y, Makiyama A, Yamazaki K, Masuishi T, Esaki T, Nakajima TE, Okuda H, Moriwaki T, Boku N. Second-line chemotherapy after early disease progression during first-line chemotherapy containing bevacizumab for patients with metastatic colorectal cancer. BMC Cancer 2021; 21:1159. [PMID: 34715820 PMCID: PMC8555183 DOI: 10.1186/s12885-021-08890-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Accepted: 10/19/2021] [Indexed: 12/28/2022] Open
Abstract
Background The ML18174 study, which showed benefits of bevacizumab (BEV) continuation beyond progression (BBP) for metastatic colorectal cancer (mCRC), excluded patients with first-line progression-free survival (PFS) shorter than 3 months. The present study was conducted to evaluate the efficacy of second-line chemotherapy after early disease progression during first-line chemotherapy containing bevacizumab. Methods The subjects of this study were mCRC patients who experienced disease progression < 100 days from commencement of first-line chemotherapy containing BEV initiated between Apr 2007 and Dec 2016. Second-line chemotherapy regimens were classified into two groups with and without BEV/other anti-angiogenic agents (BBP and non-BBP) and efficacy and safety were compared using univariate and multivariate analysis. Results Sixty-one patients were identified as subjects of this study. Baseline characteristics were numerically different between BBP (n = 37) and non-BBP (n = 25) groups, such as performance status (0–1/> 2/unknown: 89/8/3 and 56/40/4%), RAS status (wild/mutant/unknown: 32/54/16 and 76/16/8%). Response rate was 8.6% in BBP group and 9.1% in non-BBP group (p = 1.00). Median PFS was 3.9 months in BBP group and 2.8 months in non-BBP group (HR [95%CI]: 0.79 [0.46–1.34], p = 0.373, adjusted HR: 0.87 [0.41–1.82], p = 0.707). Median overall survival was 8.5 months in BBP group and 5.4 months in non-BBP group (HR 0.66 [0.38–1.12], p = 0.125, adjusted HR 0.53 [0.27–1.07], p = 0.078). Conclusion In mCRC patients who experienced early progression in first-line chemotherapy, second-line chemotherapy showed poor clinical outcomes regardless use of anti-angiogenic agents. Supplementary Information The online version contains supplementary material available at 10.1186/s12885-021-08890-6.
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Affiliation(s)
- Shun Yamamoto
- Department of Gastrointestinal Medical Oncology, National Cancer Center Hospital, Tsukiji 5-1-1, Chuo-ku, Tokyo, 1040045, Japan.,Department of Head and Neck, Esophageal Medical Oncology, National Cancer Center Hospital, Tsukiji 5-1-1, Chuo-ku, Tokyo, 1040045, Japan
| | - Kengo Nagashima
- Research Center for Medical and Health Data Science, the Institute of Statistical Mathematics, Tokyo, 1908562, Japan
| | - Takeshi Kawakami
- Division of Gastrointestinal Oncology, Shizuoka Cancer Center, Shizuoka, 4118777, Japan
| | - Seiichiro Mitani
- Department of Clinical Oncology, Aichi Cancer Center Hospital, Aichi, 4648681, Japan
| | - Masato Komoda
- Department of Gastrointestinal and Medical Oncology, National Hospital Organization Kyushu Cancer Center, Fukuoka, 8111395, Japan
| | - Yasushi Tsuji
- Department of Medical Oncology, Tonan Hospital, Hokkaido, 0600004, Japan
| | - Naoki Izawa
- Department of Clinical Oncology, St. Marianna University School of Medical Hospital, Kanagawa, 2168511, Japan
| | - Kentaro Kawakami
- Department of Medical Oncology, Keiyukai Sapporo Hospital, Hokkaido, 0030027, Japan
| | - Yoshiyuki Yamamoto
- Division of Gastroenterology, Faculty of Medicine, University of Tsukuba, Ibaraki, 3058575, Japan
| | - Akitaka Makiyama
- Department of Hematology/Oncology, Japan Community Healthcare Organization Kyushu Hospital, Fukuoka, 8068501, Japan
| | - Kentaro Yamazaki
- Division of Gastrointestinal Oncology, Shizuoka Cancer Center, Shizuoka, 4118777, Japan
| | - Toshiki Masuishi
- Department of Clinical Oncology, Aichi Cancer Center Hospital, Aichi, 4648681, Japan
| | - Taito Esaki
- Department of Gastrointestinal and Medical Oncology, National Hospital Organization Kyushu Cancer Center, Fukuoka, 8111395, Japan
| | - Takako Eguchi Nakajima
- Department of Clinical Oncology, St. Marianna University School of Medical Hospital, Kanagawa, 2168511, Japan
| | - Hiroyuki Okuda
- Department of Medical Oncology, Keiyukai Sapporo Hospital, Hokkaido, 0030027, Japan
| | - Toshikazu Moriwaki
- Division of Gastroenterology, Faculty of Medicine, University of Tsukuba, Ibaraki, 3058575, Japan
| | - Narikazu Boku
- Department of Gastrointestinal Medical Oncology, National Cancer Center Hospital, Tsukiji 5-1-1, Chuo-ku, Tokyo, 1040045, Japan. .,Department of Medical Oncology and General Medicine, IMS Hospital, Institute of Medical Science, University of Tokyo, Tokyo, 1088639, Japan.
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Tang D, Kroemer G, Kang R. Oncogenic KRAS blockade therapy: renewed enthusiasm and persistent challenges. Mol Cancer 2021; 20:128. [PMID: 34607583 PMCID: PMC8489073 DOI: 10.1186/s12943-021-01422-7] [Citation(s) in RCA: 53] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Accepted: 09/08/2021] [Indexed: 02/08/2023] Open
Abstract
Across a broad range of human cancers, gain-of-function mutations in RAS genes (HRAS, NRAS, and KRAS) lead to constitutive activity of oncoproteins responsible for tumorigenesis and cancer progression. The targeting of RAS with drugs is challenging because RAS lacks classic and tractable drug binding sites. Over the past 30 years, this perception has led to the pursuit of indirect routes for targeting RAS expression, processing, upstream regulators, or downstream effectors. After the discovery that the KRAS-G12C variant contains a druggable pocket below the switch-II loop region, it has become possible to design irreversible covalent inhibitors for the variant with improved potency, selectivity and bioavailability. Two such inhibitors, sotorasib (AMG 510) and adagrasib (MRTX849), were recently evaluated in phase I-III trials for the treatment of non-small cell lung cancer with KRAS-G12C mutations, heralding a new era of precision oncology. In this review, we outline the mutations and functions of KRAS in human tumors and then analyze indirect and direct approaches to shut down the oncogenic KRAS network. Specifically, we discuss the mechanistic principles, clinical features, and strategies for overcoming primary or secondary resistance to KRAS-G12C blockade.
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Affiliation(s)
- Daolin Tang
- The Third Affiliated Hospital, Guangzhou Medical University, Guangzhou, China. .,Department of Surgery, UT Southwestern Medical Center, Dallas, TX, USA.
| | - Guido Kroemer
- Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Université de Paris, Sorbonne Université, INSERM U1138, Institut Universitaire de France, Paris, France. .,Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, Villejuif, France. .,Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France.
| | - Rui Kang
- Department of Surgery, UT Southwestern Medical Center, Dallas, TX, USA.
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Giampieri R, Lupi A, Ziranu P, Bittoni A, Pretta A, Pecci F, Persano M, Giglio E, Copparoni C, Crocetti S, Mandolesi A, Faa G, Coni P, Scartozzi M, Berardi R. Retrospective Comparative Analysis of KRAS G12C vs. Other KRAS Mutations in mCRC Patients Treated With First-Line Chemotherapy Doublet + Bevacizumab. Front Oncol 2021; 11:736104. [PMID: 34660299 PMCID: PMC8514824 DOI: 10.3389/fonc.2021.736104] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2021] [Accepted: 09/09/2021] [Indexed: 12/28/2022] Open
Abstract
BACKGROUND KRAS mutations in metastatic colorectal cancer (mCRC) define a subset of tumors that have primary resistance to anti-EGFR-based therapy. Data concerning whether different KRAS mutations may also have a prognostic value are lacking. Furthermore, novel KRAS G12C inhibitors are currently in development. The aim of our analysis was to compare response rates in patients treated with first-line chemotherapy doublet + Bevacizumab among different KRAS variants. Secondary end-points were progression free survival (PFS) and overall survival (OS). METHODS Patients with KRAS mutated mCRC treated with either FOLFIRI/FOLFOX/XELOX + Bevacizumab were eligible for enrollment. Patients whose tumor harbored NRAS mutations or that coexpressed also BRAF mutations were excluded from this retrospective analysis. Patients' individual data were collected from patients' records. Propensity score matching (nearest method, 1:2 ratio) was used to define the two different groups of patients for comparison (KRAS G12C mutated vs other KRAS variants). Eastern Cooperative Oncology Group Performance Status (ECOG PS), sex, metastatic site of involvement, synchronous vs metachronous metastatic disease, tumor sidedness, mucinous histology, primary tumor surgery, more than two lines of treatment for metastatic disease, and radical surgery of metastases were used as matching factors. Response rate (RR) was calculated by RECIST 1.1 criteria. Both progression free-survival and overall survival were calculated by Kaplan-Meier method. Categorical variables were compared by Fisher exact test for binomial variables and by chi-square test for all other instances. The level of statistical significance p was set at 0.05 for all tests. RESULTS A total of 120 patients were assessed in the final analysis. Out of the 120 patients, 15 (12%) were KRAS G12C mutated. In the whole cohort of patients, 59/120 (49%) had partial response (PR), 42/120 (35%) had stable disease (SD), and 19/120 (16%) had progressive disease (PD) as the best response. In KRAS G12C patients, 4/15 (27%) had PR, 6/15 (40%) had SD, and the remaining 5/15 (33%) had PD as the best response. In patients with other KRAS mutations, 55/105 (52%) had PR, 37/105 (35%) had SD, and the remaining 13/105 (12%) had PD as the best response. The difference in RR between the two groups of patients was statistically significant (p=0.017). On the other hand, no difference in PFS (p=0.76) and OS (p=0.56) was observed. After matching procedures, the difference in response rates between KRAS G12C mutated patients vs the matched cohort of patients with other KRAS mutations remained statistically significant (p=0.016). KRAS G12C mutations were not associated with differences in sites of metastatic involvement, sex, and ECOG PS. On the other hand, synchronous vs metachronous metastatic disease (p=0.039), age > 75 years (p=0.043), and mucinous histology (p=0.008) were more frequent in G12C mutated tumors. CONCLUSIONS In our cohort of patients, it was observed that KRAS G12C mutations are associated with worse response rates compared to other KRAS variants when treated with standard chemotherapy doublet + Bevacizumab. On the other hand, both PFS and OS were not significantly different. Based on these findings, we believe that new treatment options focused on KRAS G12C inhibition should be tested mainly in first-line setting and in addition to standard chemotherapy doublet + Bevacizumab for mCRC patients, as they might "fill the gap" in response rates that was seen in our study.
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Affiliation(s)
- Riccardo Giampieri
- Clinica Oncologica—Dipartimento Scienze Cliniche e Molecolari—Università Politecnica delle Marche, Ancona, Italy
- Clinica Oncologica—Azienda Ospedaliera Universitaria Ospedali Riuniti di Ancona, Ancona, Italy
| | - Alessio Lupi
- Clinica Oncologica—Dipartimento Scienze Cliniche e Molecolari—Università Politecnica delle Marche, Ancona, Italy
| | - Pina Ziranu
- Oncologia, Università ed Azienda Ospedaliera Universitaria di Cagliari, Cagliari, Italy
| | - Alessandro Bittoni
- Clinica Oncologica—Azienda Ospedaliera Universitaria Ospedali Riuniti di Ancona, Ancona, Italy
| | - Andrea Pretta
- Oncologia, Università ed Azienda Ospedaliera Universitaria di Cagliari, Cagliari, Italy
- Oncologia Medica, Università “la Sapienza” di Roma, Rome, Italy
| | - Federica Pecci
- Clinica Oncologica—Dipartimento Scienze Cliniche e Molecolari—Università Politecnica delle Marche, Ancona, Italy
| | - Mara Persano
- Oncologia, Università ed Azienda Ospedaliera Universitaria di Cagliari, Cagliari, Italy
| | - Enrica Giglio
- Clinica Oncologica—Dipartimento Scienze Cliniche e Molecolari—Università Politecnica delle Marche, Ancona, Italy
| | - Cecilia Copparoni
- Clinica Oncologica—Dipartimento Scienze Cliniche e Molecolari—Università Politecnica delle Marche, Ancona, Italy
| | - Sonia Crocetti
- Clinica Oncologica—Dipartimento Scienze Cliniche e Molecolari—Università Politecnica delle Marche, Ancona, Italy
| | - Alessandra Mandolesi
- Anatomia Patologica—Azienda Ospedaliera Universitaria Ospedali Riuniti di Ancona, Ancona, Italy
| | - Gavino Faa
- Anatomia Patologica—Dipartimento di Scienze Mediche e Sanità Pubblica—Università di Cagliari, Cagliari, Italy
| | - Pierpaolo Coni
- Anatomia Patologica—Dipartimento di Scienze Mediche e Sanità Pubblica—Università di Cagliari, Cagliari, Italy
| | - Mario Scartozzi
- Oncologia, Università ed Azienda Ospedaliera Universitaria di Cagliari, Cagliari, Italy
| | - Rossana Berardi
- Clinica Oncologica—Dipartimento Scienze Cliniche e Molecolari—Università Politecnica delle Marche, Ancona, Italy
- Clinica Oncologica—Azienda Ospedaliera Universitaria Ospedali Riuniti di Ancona, Ancona, Italy
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Loree JM, Wang Y, Syed MA, Sorokin AV, Coker O, Xiu J, Weinberg BA, Vanderwalde AM, Tesfaye A, Raymond VM, Miron B, Tarcic G, Zelichov O, Broaddus RR, Ng PKS, Jeong KJ, Tsang YH, Mills GB, Overman MJ, Grothey A, Marshall JL, Kopetz S. Clinical and Functional Characterization of Atypical KRAS/ NRAS Mutations in Metastatic Colorectal Cancer. Clin Cancer Res 2021; 27:4587-4598. [PMID: 34117033 PMCID: PMC8364867 DOI: 10.1158/1078-0432.ccr-21-0180] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Revised: 04/29/2021] [Accepted: 06/09/2021] [Indexed: 01/13/2023]
Abstract
PURPOSE Mutations in KRAS/NRAS (RAS) predict lack of anti-EGFR efficacy in metastatic colorectal cancer (mCRC). However, it is unclear if all RAS mutations have similar impact, and atypical mutations beyond those in standard guidelines exist. EXPERIMENTAL DESIGN We reviewed 7 tissue and 1 cell-free DNA cohorts of 9,485 patients to characterize atypical RAS variants. Using an in vitro cell-based assay (functional annotation for cancer treatment), Ba/F3 transformation, and in vivo xenograft models of transduced isogenic clones, we assessed signaling changes across mutations. RESULTS KRAS exon 2, extended RAS, and atypical RAS mutations were noted in 37.8%, 9.5%, and 1.2% of patients, respectively. Among atypical variants, KRAS L19F, Q22K, and D33E occurred at prevalence ≥0.1%, whereas no NRAS codon 117/146 and only one NRAS codon 59 mutation was noted. Atypical RAS mutations had worse overall survival than RAS/BRAF wild-type mCRC (HR, 2.90; 95% confidence interval, 1.24-6.80; P = 0.014). We functionally characterized 114 variants with the FACT assay. All KRAS exon 2 and extended RAS mutations appeared activating. Of 57 atypical RAS variants characterized, 18 (31.6%) had signaling below wild-type, 23 (40.4%) had signaling between wild-type and activating control, and 16 (28.1%) were hyperactive beyond the activating control. Ba/F3 transformation (17/18 variants) and xenograft model (7/8 variants) validation was highly concordant with FACT results, and activating atypical variants were those that occurred at highest prevalence in clinical cohorts. CONCLUSIONS We provide best available evidence to guide treatment when atypical RAS variants are identified. KRAS L19F, Q22K, D33E, and T50I are more prevalent than many guideline-included RAS variants and functionally relevant.
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Affiliation(s)
| | | | - Muddassir A Syed
- The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Alexey V Sorokin
- The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Oluwadara Coker
- The University of Texas MD Anderson Cancer Center, Houston, Texas
| | | | - Benjamin A Weinberg
- Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC
| | | | | | | | | | | | | | | | | | - Kang Jin Jeong
- Oregon Health Sciences University Knight Cancer Institute, Portland, Oregon
| | - Yiu Huen Tsang
- Oregon Health Sciences University Knight Cancer Institute, Portland, Oregon
| | - Gordon B Mills
- Oregon Health Sciences University Knight Cancer Institute, Portland, Oregon
| | | | | | | | - Scott Kopetz
- The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Chen K, Zhang Y, Qian L, Wang P. Emerging strategies to target RAS signaling in human cancer therapy. J Hematol Oncol 2021; 14:116. [PMID: 34301278 PMCID: PMC8299671 DOI: 10.1186/s13045-021-01127-w] [Citation(s) in RCA: 101] [Impact Index Per Article: 25.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Accepted: 07/12/2021] [Indexed: 02/07/2023] Open
Abstract
RAS mutations (HRAS, NRAS, and KRAS) are among the most common oncogenes, and around 19% of patients with cancer harbor RAS mutations. Cells harboring RAS mutations tend to undergo malignant transformation and exhibit malignant phenotypes. The mutational status of RAS correlates with the clinicopathological features of patients, such as mucinous type and poor differentiation, as well as response to anti-EGFR therapies in certain types of human cancers. Although RAS protein had been considered as a potential target for tumors with RAS mutations, it was once referred to as a undruggable target due to the consecutive failure in the discovery of RAS protein inhibitors. However, recent studies on the structure, signaling, and function of RAS have shed light on the development of RAS-targeting drugs, especially with the approval of Lumakras (sotorasib, AMG510) in treatment of KRASG12C-mutant NSCLC patients. Therefore, here we fully review RAS mutations in human cancer and especially focus on emerging strategies that have been recently developed for RAS-targeting therapy.
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Affiliation(s)
- Kun Chen
- Department of Integrative Oncology, Fudan University Shanghai Cancer Center, 270 Dong An Road, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Yalei Zhang
- Department of Integrative Oncology, Fudan University Shanghai Cancer Center, 270 Dong An Road, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Ling Qian
- Department of Integrative Oncology, Fudan University Shanghai Cancer Center, 270 Dong An Road, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Peng Wang
- Department of Integrative Oncology, Fudan University Shanghai Cancer Center, 270 Dong An Road, Shanghai, 200032, China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
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Mathematical Modeling to Study KRAS Mutant-Specific Responses to Pathway Inhibition. METHODS IN MOLECULAR BIOLOGY (CLIFTON, N.J.) 2021; 2262:311-321. [PMID: 33977486 DOI: 10.1007/978-1-0716-1190-6_19] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
This chapter will describe how mathematical modeling allows the RAS pathway to be studied with computational experiments. The mathematical model utilized simulates the biochemical reactions that regulate RAS signaling. This type of model incorporates knowledge of reaction mechanisms, including measured quantitative parameters that characterize these reactions for both wild-type and mutant RAS proteins. For an illustrative example, this chapter focuses on how modeling provided new insights that helped solve a problem that challenged the RAS community for nearly a decade: why do colorectal cancers with the KRAS G13D mutation, but not the other common KRAS mutations, benefit from EGFR inhibition? The methods described include computational dose-response experiments and the use of "computational chimeric" RAS mutants.
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Morelli C, Formica V, Riondino S, Russo A, Ferroni P, Guadagni F, Roselli M. Irinotecan or Oxaliplatin: Which is the First Move for the Mate? Curr Med Chem 2021; 28:3158-3172. [PMID: 33069191 DOI: 10.2174/0929867327666201016124950] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2020] [Revised: 09/02/2020] [Accepted: 09/06/2020] [Indexed: 11/22/2022]
Abstract
OBJECTIVES The aim of the present review is to discuss the potential link between RAS, BRAF and microsatellite instability (MSI) mutational patterns and chemotherapeutic agent efficacy [Irinotecan (IRI) vs. Oxaliplatin (OXA)], and how this can potentially influence the choice of the chemotherapy backbone. METHODS Following a review of the research literature, all pertinent articles published in the core journals were selected for the study. The inclusion criteria regarded relevant clinical and pre-clinical studies on the topic of interest (Relationship of OXA and IRI to KRAS/BRAF mutations and MSI). RESULTS Excision repair cross complementation group 1 (ERCC1) expression is inhibited by KRAS mutation, making tumor cells more sensitive to OXA. Results from OPUS, COIN and PRIME trials support that no conclusive data are available for BRAF mutant population because of the small number of patients. Enhanced IRI cytotoxicity to MSI cell lines is due to the participation of some of the mismatch repair (MMR) components in various DNA repair processes and their role in the maintenance of the pro-apoptotic effect of IRI and G2/M cell arrest. CONCLUSION OXA and IRI are indispensable drugs for mCRC treatment and their selection must be as careful as that of targeted agents. We suggest taking into consideration the interaction between known genomic alterations and OXA and IRI activity to personalize chemotherapy in mCRC patients.
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Affiliation(s)
- Cristina Morelli
- Department of Systems Medicine, Medical Oncology Unit, Tor Vergata Clinical Center, Tor Vergata University of Rome, Viale Oxford 81, 00133, Rome, Italy
| | - Vincenzo Formica
- Department of Systems Medicine, Medical Oncology Unit, Tor Vergata Clinical Center, Tor Vergata University of Rome, Viale Oxford 81, 00133, Rome, Italy
| | - Silvia Riondino
- Department of Systems Medicine, Medical Oncology Unit, Tor Vergata Clinical Center, Tor Vergata University of Rome, Viale Oxford 81, 00133, Rome, Italy
| | - Antonio Russo
- Department of Surgical, Oncological and Stomatological Sciences, University of Palermo, Via del Vespro 129, 90127 Palermo, Italy
| | - Patrizia Ferroni
- BioBIM (InterInstitutional Multidisciplinary Biobank), IRCCS San Raffaele Pisana, Via di Val Cannuta 247, 00166 Rome, Italy
| | - Fiorella Guadagni
- BioBIM (InterInstitutional Multidisciplinary Biobank), IRCCS San Raffaele Pisana, Via di Val Cannuta 247, 00166 Rome, Italy
| | - Mario Roselli
- Department of Systems Medicine, Medical Oncology Unit, Tor Vergata Clinical Center, Tor Vergata University of Rome, Viale Oxford 81, 00133, Rome, Italy
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KRAS and NRAS genes mutations as biomarkers in the therapy of colorectal cancer and the basic methods of their detection. КЛИНИЧЕСКАЯ ПРАКТИКА 2021. [DOI: 10.17816/clinpract63875] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Determination of the mutations' status in the KRAS and NRAS genes is a necessary requirement in the treatment of patients with colorectal cancer (CRC). Patients with certain mutations in the KRAS and NRAS genes are resistant to anti-EGFR drug therapy and have a lower median survival rate than those with WT (wild type) genotypes, that indicates a negative prognosis in the case when mutations are present. Currently, there are no registered targeted drugs for carriers of the KRAS and NRAS genes mutations, however, preparations based on small molecules are under way. The gold standard for detecting mutations in the KRAS and NRAS genes is the analysis of the biopsy material in paraffin blocks. However, this method has significant limitations that can be circumvented by the analysis of circulating tumor DNA a promising new method in the diagnosis of colorectal cancer.
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Chung C. Predictive and prognostic biomarkers with therapeutic targets in colorectal cancer: A 2021 update on current development, evidence, and recommendation. J Oncol Pharm Pract 2021; 28:850-869. [PMID: 33832365 DOI: 10.1177/10781552211005525] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Although therapeutically actionable molecular alterations are widely distributed across many cancer types, only a handful of them show evidence of clinical utility and are recommended for routine clinical practice in the management of cancers of colon and rectum (CRC). This 2021 update aims to provide a succinct summary on the use of prognostic and/or predictive biomarkers (expanded RAS, BRAF, microsatellite-high [MSI-H] or deficient mismatch repair [dMMR], neurotrophic tyrosine receptor kinase [NTRK] fusion genes, and human epidermal growth factor receptor type II [HER2] gene amplification) associated with CRC. Therapeutic implications of each relevant predictive or prognostic biomarker for patients with CRC are described, along with discussion on new developments on (1) biomarker-driven therapies such as testing of BRAF, MLH1 promoter methylation and MMR germline genes in differentiating sporadic CRC or hereditary conditions such as Lynch syndrome; (2) first-line use of immune checkpoint inhibitors in metastatic CRC; (3) risk stratification and therapy selection based on primary tumor location (left-sided vs. right-sided colon cancer); (3) atypical BRAF mutations; (4) use of EGFR directed therapy in the perioperative oligometastatic disease setting; (5) re-challenge of EGFR directed therapy and (6) personalizing therapy of fluoropyrimidine and irinotecan based on new evidence in pharmacogenomic testing. Data are collected and analyzed from available systematic reviews and meta-analyses of treatments with known therapeutic targets in CRC, which may be associated with predictive and/or prognostic biomarkers. Discussions are presented in an application-based format, with goal to empower pharmacists or other clinicians to gain awareness and understanding in biomarker-driven cancer therapy issues.
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Affiliation(s)
- Clement Chung
- 23530Houston Methodist West Hospital, Houston, TX, USA
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44
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Avolio M, Trusolino L. Rational Treatment of Metastatic Colorectal Cancer: A Reverse Tale of Men, Mice, and Culture Dishes. Cancer Discov 2021; 11:1644-1660. [PMID: 33820776 DOI: 10.1158/2159-8290.cd-20-1531] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Revised: 01/04/2021] [Accepted: 02/01/2021] [Indexed: 11/16/2022]
Abstract
Stratification of colorectal cancer into subgroups with different response to therapy was initially guided by descriptive associations between specific biomarkers and treatment outcome. Recently, preclinical models based on propagatable patient-derived tumor samples have yielded an improved understanding of disease biology, which has facilitated the functional validation of correlative information and the discovery of novel response determinants, therapeutic targets, and mechanisms of tumor adaptation and drug resistance. We review the contribution of patient-derived models to advancing colorectal cancer characterization, discuss their influence on clinical decision-making, and highlight emerging challenges in the interpretation and clinical transferability of results obtainable with such approaches. SIGNIFICANCE: Association studies in patients with colorectal cancer have led to the identification of response biomarkers, some of which have been implemented as companion diagnostics for therapeutic decisions. By enabling biological investigation in a clinically relevant experimental context, patient-derived colorectal cancer models have proved useful to examine the causal role of such biomarkers in dictating drug sensitivity and are providing fresh knowledge on new actionable targets, dynamics of tumor evolution and adaptation, and mechanisms of drug resistance.
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Affiliation(s)
- Marco Avolio
- Department of Oncology, University of Torino, Candiolo, Torino, Italy.,Candiolo Cancer Institute - FPO IRCCS, Candiolo, Torino, Italy
| | - Livio Trusolino
- Department of Oncology, University of Torino, Candiolo, Torino, Italy. .,Candiolo Cancer Institute - FPO IRCCS, Candiolo, Torino, Italy
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45
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Benson AB, Venook AP, Al-Hawary MM, Arain MA, Chen YJ, Ciombor KK, Cohen S, Cooper HS, Deming D, Farkas L, Garrido-Laguna I, Grem JL, Gunn A, Hecht JR, Hoffe S, Hubbard J, Hunt S, Johung KL, Kirilcuk N, Krishnamurthi S, Messersmith WA, Meyerhardt J, Miller ED, Mulcahy MF, Nurkin S, Overman MJ, Parikh A, Patel H, Pedersen K, Saltz L, Schneider C, Shibata D, Skibber JM, Sofocleous CT, Stoffel EM, Stotsky-Himelfarb E, Willett CG, Gregory KM, Gurski LA. Colon Cancer, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw 2021; 19:329-359. [PMID: 33724754 DOI: 10.6004/jnccn.2021.0012] [Citation(s) in RCA: 918] [Impact Index Per Article: 229.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
This selection from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Colon Cancer focuses on systemic therapy options for the treatment of metastatic colorectal cancer (mCRC), because important updates have recently been made to this section. These updates include recommendations for first-line use of checkpoint inhibitors for mCRC, that is deficient mismatch repair/microsatellite instability-high, recommendations related to the use of biosimilars, and expanded recommendations for biomarker testing. The systemic therapy recommendations now include targeted therapy options for patients with mCRC that is HER2-amplified, or BRAF V600E mutation-positive. Treatment and management of nonmetastatic or resectable/ablatable metastatic disease are discussed in the complete version of the NCCN Guidelines for Colon Cancer available at NCCN.org. Additional topics covered in the complete version include risk assessment, staging, pathology, posttreatment surveillance, and survivorship.
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Affiliation(s)
- Al B Benson
- 1Robert H. Lurie Comprehensive Cancer Center of Northwestern University
| | - Alan P Venook
- 2UCSF Helen Diller Family Comprehensive Cancer Center
| | | | | | | | | | - Stacey Cohen
- 6Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance
| | | | | | - Linda Farkas
- 9UT Southwestern Simmons Comprehensive Cancer Center
| | | | | | | | | | | | | | - Steven Hunt
- 16Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine
| | | | | | - Smitha Krishnamurthi
- 19Case Comprehensive Cancer Center/University Hospitals Seidman Cancer Center and Cleveland Clinic Taussig Cancer Institute
| | | | | | - Eric D Miller
- 22The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute
| | - Mary F Mulcahy
- 1Robert H. Lurie Comprehensive Cancer Center of Northwestern University
| | | | | | | | | | - Katrina Pedersen
- 16Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine
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Liu J, Sun M, Cho KB, Gao X, Guo B. A CRISPR-Cas9 repressor for epigenetic silencing of KRAS. Pharmacol Res 2021; 164:105304. [PMID: 33202255 PMCID: PMC8422974 DOI: 10.1016/j.phrs.2020.105304] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2020] [Revised: 10/20/2020] [Accepted: 11/10/2020] [Indexed: 01/10/2023]
Abstract
KRAS is one of the most frequently mutated oncogenes in cancers. Currently no direct and effective anti-KRAS therapies are available. Using the powerful CRISPR-Cas9 technology to target the mutant KRAS promoter, we designed an epigenetic repressor to silence KRAS through epigenome editing. Catalytically dead Cas9 (dCas9) functioned as a DNA binding device, which was fused with a transcriptional repressor histone deacetylase 1 (HDAC1). We designed a panel of three CRISPR RNAs (crRNAs) covering 1500-bp range of the KRAS promoter and identified that crRNA1 and crRNA2 efficiently silenced KRAS. The suppression of K-Ras resulted in a significant inhibition of cell growth, suppression of colony formation in soft agar and induction of cell death in cancer cells with KRAS mutations. In addition, the chromatin immunoprecipitation (ChIP) assay demonstrated dCas9-HDAC1 modified histone acetylation on the KRAS promoter. Furthermore, transfection of dCas9-HDAC1 protein and gRNA ribonucleoprotein complex also inhibited K-Ras and suppressed cell proliferation. In summary, we have developed a new strategy that combines CRISPR-Cas9 technology with HDAC1 epigenetic silencing to target cancers driven by KRAS mutations.
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Affiliation(s)
- Jingwen Liu
- Department of Pharmacological and Pharmaceutical Sciences, University of Houston, Houston, TX, 77204, United States
| | - Meiyan Sun
- Department of Pharmacological and Pharmaceutical Sciences, University of Houston, Houston, TX, 77204, United States; College of Laboratory Medicine, Jilin Medical University, Jilin Province, 132013, China.
| | - Kwang Bog Cho
- Department of Pharmacological and Pharmaceutical Sciences, University of Houston, Houston, TX, 77204, United States
| | - Xiang Gao
- Department of Pharmacological and Pharmaceutical Sciences, University of Houston, Houston, TX, 77204, United States
| | - Bin Guo
- Department of Pharmacological and Pharmaceutical Sciences, University of Houston, Houston, TX, 77204, United States.
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Mehmood A, Kaushik AC, Wang Q, Li CD, Wei DQ. Bringing Structural Implications and Deep Learning-Based Drug Identification for KRAS Mutants. J Chem Inf Model 2021; 61:571-586. [PMID: 33513018 DOI: 10.1021/acs.jcim.0c00488] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Colorectal cancer is considered one of the leading causes of death that is linked with the Kirsten Rat Sarcoma (KRAS) harboring codons 13 and 61 mutations. The objective for this study is to search for clinically important codon 61 mutations and analyze how they affect the protein structural dynamics. Additionally, a deep-learning approach is used to carry out a similarity search for potential compounds that might have a comparatively better affinity. Public databases like The Cancer Genome Atlas and Genomic Data Commons were accessed for obtaining the data regarding mutations that are associated with colon cancer. Multiple analysis such as genomic alteration landscape, survival analysis, and systems biology-based kinetic simulations were carried out to predict dynamic changes for the selected mutations. Additionally, a molecular dynamics simulation of 100 ns for all the seven shortlisted codon 61 mutations have been conducted, which revealed noticeable deviations. Finally, the deep learning-based predicted compounds were docked with the KRAS 3D conformer, showing better affinity and good docking scores as compared to the already existing drugs. Taking together the outcomes of systems biology and molecular dynamics, it is observed that the reported mutations in the SII region are highly detrimental as they have an immense impact on the protein sensitive sites' native conformation and overall stability. The drugs reported in this study show increased performance and are encouraged to be used for further evaluation regarding the situation that ascends as a result of KRAS mutations.
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Affiliation(s)
- Aamir Mehmood
- Department of Bioinformatics and Biostatistics, State Key Laboratory of Microbial Metabolism and School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, 800 Dongchuan Road, Minhang District, Shanghai 200240, China.,Peng Cheng Laboratory, Vanke Cloud City Phase I Building 8, Xili Street, Nanshan District, Shenzhen, Guangdong, 518055, P. R. China
| | - Aman Chandra Kaushik
- Wuxi School of Medicine, Jiangnan University, Li Lake Avenue, Wuxi, Jiangsu 214122, China
| | - Qiankun Wang
- Department of Bioinformatics and Biostatistics, State Key Laboratory of Microbial Metabolism and School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, 800 Dongchuan Road, Minhang District, Shanghai 200240, China
| | - Cheng-Dong Li
- Department of Bioinformatics and Biostatistics, State Key Laboratory of Microbial Metabolism and School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, 800 Dongchuan Road, Minhang District, Shanghai 200240, China
| | - Dong-Qing Wei
- Department of Bioinformatics and Biostatistics, State Key Laboratory of Microbial Metabolism and School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, 800 Dongchuan Road, Minhang District, Shanghai 200240, China.,Peng Cheng Laboratory, Vanke Cloud City Phase I Building 8, Xili Street, Nanshan District, Shenzhen, Guangdong, 518055, P. R. China
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48
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Wu X, Li Y, Chen X, Huang Y, He L, Zhao K, Huang X, Zhang W, Huang Y, Li Y, Dong M, Huang J, Xia T, Liang C, Liu Z. Deep Learning Features Improve the Performance of a Radiomics Signature for Predicting KRAS Status in Patients with Colorectal Cancer. Acad Radiol 2020; 27:e254-e262. [PMID: 31982342 DOI: 10.1016/j.acra.2019.12.007] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2019] [Revised: 12/07/2019] [Accepted: 12/11/2019] [Indexed: 12/19/2022]
Abstract
RATIONALE AND OBJECTIVES We assess the performance of a model combining a deep convolutional neural network and a hand-crafted radiomics signature for predicting KRAS status in patients with colorectal cancer (CRC). MATERIALS AND METHODS The primary cohort consisted of 279 patients with clinicopathologically confirmed CRC between April 2011 and April 2015. Portal venous phase computed tomographic images were analyzed to extract traditional hand-crafted radiomics features as well as deep learning features. A Wilcoxon rank sum test, the minimum redundancy maximum relevance algorithm, and multivariable logistic regression analysis were used to select features and build a radiomics signature. A combined model was then developed using multivariable logistic regression analysis. An independent validation cohort of 119 patients from May 2015 to April 2016 was used to confirm the combined model's predictive performance. RESULTS The C-index of hand-crafted radiomics signature's discriminative ability was 0.719 (95% confidence interval, CI: 0.658-0.776) for the primary cohort and 0.720 (95% CI: 0.625-0.813) for the validation cohort. The C-index of the deep radiomics signature's discriminative ability was 0.754 (95% CI: 0.696-0.813) for the primary cohort and 0.786 (95% CI: 0.702-0.863) for the validation cohort. The combined model, which merged the hand-crafted radiomics features and deep radiomics features, achieve a C-index of 0.815 (95% CI: 0.766-0.868) for the primary cohort and 0.832 (95% CI: 0.762-0.905) for the validation cohort. CONCLUSION This study presents a model that incorporates the hand-crafted and deep radiomics signature, which can be used for individualized preoperative prediction of KRAS mutations in patients with CRC.
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Marshall CB, KleinJan F, Gebregiworgis T, Lee KY, Fang Z, Eves BJ, Liu NF, Gasmi-Seabrook GMC, Enomoto M, Ikura M. NMR in integrated biophysical drug discovery for RAS: past, present, and future. JOURNAL OF BIOMOLECULAR NMR 2020; 74:531-554. [PMID: 32804298 DOI: 10.1007/s10858-020-00338-6] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/14/2020] [Accepted: 07/16/2020] [Indexed: 06/11/2023]
Abstract
Mutations in RAS oncogenes occur in ~ 30% of human cancers, with KRAS being the most frequently altered isoform. RAS proteins comprise a conserved GTPase domain and a C-terminal lipid-modified tail that is unique to each isoform. The GTPase domain is a 'switch' that regulates multiple signaling cascades that drive cell growth and proliferation when activated by binding GTP, and the signal is terminated by GTP hydrolysis. Oncogenic RAS mutations disrupt the GTPase cycle, leading to accumulation of the activated GTP-bound state and promoting proliferation. RAS is a key target in oncology, however it lacks classic druggable pockets and has been extremely challenging to target. RAS signaling has thus been targeted indirectly, by harnessing key downstream effectors as well as upstream regulators, or disrupting the proper membrane localization required for signaling, by inhibiting either lipid modification or 'carrier' proteins. As a small (20 kDa) protein with multiple conformers in dynamic equilibrium, RAS is an excellent candidate for NMR-driven characterization and screening for direct inhibitors. Several molecules have been discovered that bind RAS and stabilize shallow pockets through conformational selection, and recent compounds have achieved substantial improvements in affinity. NMR-derived insight into targeting the RAS-membrane interface has revealed a new strategy to enhance the potency of small molecules, while another approach has been development of peptidyl inhibitors that bind through large interfaces rather than deep pockets. Remarkable progress has been made with mutation-specific covalent inhibitors that target the thiol of a G12C mutant, and these are now in clinical trials. Here we review the history of RAS inhibitor development and highlight the utility of NMR and integrated biophysical approaches in RAS drug discovery.
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Affiliation(s)
- Christopher B Marshall
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, M5G 1L7, Canada.
| | - Fenneke KleinJan
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, M5G 1L7, Canada
| | - Teklab Gebregiworgis
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, M5G 1L7, Canada
| | - Ki-Young Lee
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, M5G 1L7, Canada
| | - Zhenhao Fang
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, M5G 1L7, Canada
- Department of Medical Biophysics, University of Toronto, Toronto, ON, M5G 1L7, Canada
| | - Ben J Eves
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, M5G 1L7, Canada
| | - Ningdi F Liu
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, M5G 1L7, Canada
- Department of Medical Biophysics, University of Toronto, Toronto, ON, M5G 1L7, Canada
| | | | - Masahiro Enomoto
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, M5G 1L7, Canada
| | - Mitsuhiko Ikura
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, M5G 1L7, Canada.
- Department of Medical Biophysics, University of Toronto, Toronto, ON, M5G 1L7, Canada.
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50
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Zhang K, Deng R, Gao H, Teng X, Li J. Lighting up single-nucleotide variation in situ in single cells and tissues. Chem Soc Rev 2020; 49:1932-1954. [PMID: 32108196 DOI: 10.1039/c9cs00438f] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The ability to 'see' genetic information directly in single cells can provide invaluable insights into complex biological systems. In this review, we discuss recent advances of in situ imaging technologies for visualizing the subtlest sequence alteration, single-nucleotide variation (SNV), at single-cell level. The mechanism of recently developed methods for SNV discrimination are summarized in detail. With recent developments, single-cell SNV imaging methods have opened a new door for studying the heterogenous and stochastic genetic information in individual cells. Furthermore, SNV imaging can be used on morphologically preserved tissue, which can provide information on histological context for gene expression profiling in basic research and genetic diagnosis. Moreover, the ability to visualize SNVs in situ can be further developed into in situ sequencing technology. We expect this review to inspire more research work into in situ SNV imaging technologies for investigating cellular phenotypes and gene regulation at single-nucleotide resolution, and developing new clinical and biomedical applications.
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Affiliation(s)
- Kaixiang Zhang
- Department of Chemistry, Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, Beijing Key Laboratory for Microanalytical Methods and Instrumentation, Tsinghua University, Beijing 100084, China. and School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Ruijie Deng
- Department of Chemistry, Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, Beijing Key Laboratory for Microanalytical Methods and Instrumentation, Tsinghua University, Beijing 100084, China.
| | - Hua Gao
- Department of Chemistry, Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, Beijing Key Laboratory for Microanalytical Methods and Instrumentation, Tsinghua University, Beijing 100084, China. and Department of Pathogeny Biology, Medical College, Zhengzhou University, Zhengzhou 450001, China
| | - Xucong Teng
- Department of Chemistry, Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, Beijing Key Laboratory for Microanalytical Methods and Instrumentation, Tsinghua University, Beijing 100084, China.
| | - Jinghong Li
- Department of Chemistry, Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, Beijing Key Laboratory for Microanalytical Methods and Instrumentation, Tsinghua University, Beijing 100084, China.
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