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Zhang Y, Fan W, Su F, Zhang X, Du Y, Li W, Gao Y, Hu W, Zhao J. Discussion on the mechanism of HER2 resistance in esophagogastric junction and gastric cancer in the era of immunotherapy. Hum Vaccin Immunother 2025; 21:2459458. [PMID: 39875210 PMCID: PMC11776468 DOI: 10.1080/21645515.2025.2459458] [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: 11/06/2024] [Revised: 01/11/2025] [Accepted: 01/24/2025] [Indexed: 01/30/2025] Open
Abstract
Human epidermal growth factor receptor 2 (HER2) is a critical biomarker and therapeutic target in gastric/gastroesophageal junction (G/GEJ) cancers, despite the initial success of HER2-targeted therapies, such as trastuzumab, resistance to these drugs has emerged as a major impediment to effective long-term treatment. This review examines the mechanisms of drug resistance in HER2-positive G/GEJ cancer, the primary mechanisms of resistance explored include alterations in the HER2 receptor itself, such as mutations and changes in expression levels, as well as downstream signaling pathways, and interactions with the tumor microenvironment (TME). Furthermore, the review discusses the Novel therapeutic approaches, including the use of antibody-drug conjugates (ADCs) and combination therapies are assessed for their potential to enhance outcomes. By integrating recent research findings and clinical trials, this review aims to provide oncologists and researchers with insights into developing more effective treatments for patients with drug-resistant HER2-positive G/GEJ cancer.
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Affiliation(s)
- Yan Zhang
- Department of Oncology, Changzhi People’s Hospital Affiliated to Changzhi Medical College, Changzhi, Shanxi, China
- Graduate School, Changzhi Medical College, Changzhi, Shanxi, China
| | - Wenxuan Fan
- Department of Oncology, Changzhi People’s Hospital Affiliated to Changzhi Medical College, Changzhi, Shanxi, China
- Graduate School, Shanxi Medical University, Taiyuan, Shanxi, China
| | - Fei Su
- Department of Oncology, Changzhi People’s Hospital Affiliated to Changzhi Medical College, Changzhi, Shanxi, China
- Graduate School, Shanxi Medical University, Taiyuan, Shanxi, China
| | - Xiaoling Zhang
- Department of Oncology, Changzhi People’s Hospital Affiliated to Changzhi Medical College, Changzhi, Shanxi, China
| | - Yunyi Du
- Department of Oncology, Changzhi People’s Hospital Affiliated to Changzhi Medical College, Changzhi, Shanxi, China
| | - Weiling Li
- Department of Oncology, Changzhi People’s Hospital Affiliated to Changzhi Medical College, Changzhi, Shanxi, China
- Graduate School, Changzhi Medical College, Changzhi, Shanxi, China
| | - Yangjun Gao
- Department of Oncology, Changzhi People’s Hospital Affiliated to Changzhi Medical College, Changzhi, Shanxi, China
| | - Wenqing Hu
- Department of Gastrointestinal Surgery, Changzhi People’s Hospital Affiliated to Changzhi Medical College, Changzhi, Shanxi, China
| | - Jun Zhao
- Department of Oncology, Changzhi People’s Hospital Affiliated to Changzhi Medical College, Changzhi, Shanxi, China
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Cai J, Wang W, Cong D, Bai Y, Zhang W. Development of treatment strategies for advanced HER2-positive gastric cancer: Insights from clinical trials. Crit Rev Oncol Hematol 2025; 207:104617. [PMID: 39805409 DOI: 10.1016/j.critrevonc.2025.104617] [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: 04/05/2024] [Revised: 01/06/2025] [Accepted: 01/08/2025] [Indexed: 01/16/2025] Open
Abstract
HER2-positive gastric cancer (GC), a unique molecular subtype, has garnered significant interest in recent years. Here, we review clinical trial data on advanced HER2-positive GC from the past 15 years. Trastuzumab plus standard chemotherapy remain the first-line treatment. The initial survival benefits conferred by immune checkpoint inhibitors plus trastuzumab and standard chemotherapy are encouraging. The combination of ramucirumab and mono-chemotherapy, as well as the antibody conjugated drug trastuzumab deruxtecan, is the recommended second-line regimen. Treatment with immune checkpoint inhibitors plus ramucirumab and mono-chemotherapy shows promise. Despite the limited treatment options for third line and beyond, development of novel therapeutic strategies is expected. Although clinical cure of advanced HER2-positive GC is unlikely, current clinical studies offer valuable insight into regimens that prolong survival.
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Affiliation(s)
- Jing Cai
- Department of Pediatrics, China-Japan Union Hospital of Jilin University, Changchun 130033, China
| | - Wanning Wang
- Department of Nephrology, the First Hospital of Jilin University, Changchun 130021, China
| | - Dan Cong
- Department of Hematology and Oncology, China-Japan Union Hospital of Jilin University, Changchun 130033, China
| | - Yuansong Bai
- Department of Hematology and Oncology, China-Japan Union Hospital of Jilin University, Changchun 130033, China
| | - Wenlong Zhang
- Department of Hematology and Oncology, China-Japan Union Hospital of Jilin University, Changchun 130033, China.
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Dong Y, Yang G, Yang Y, Zhang S, Wang Y, Xu H. Dynamic characterization of circulating tumor DNA in HER2-altered advanced non-small cell lung cancer treated with pyrotinib and apatinib: Exploratory biomarker analysis from PATHER2 study. Lung Cancer 2025; 200:108062. [PMID: 39827483 DOI: 10.1016/j.lungcan.2024.108062] [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: 07/04/2024] [Revised: 12/01/2024] [Accepted: 12/14/2024] [Indexed: 01/22/2025]
Abstract
BACKGROUND HER2 mutations are critical drivers of non-small cell lung cancer (NSCLC), affecting 2 %-3 % of patients and often leads to poor prognosis and limited response to conventional therapies. This study investigates the genomic characteristics and prognostic relevance of dynamic circulating tumor DNA (ctDNA) monitoring in advanced NSCLC patients with HER2 mutations treated with pyrotinib and apatinib. METHODS The PATHER2 study included 33 advanced NSCLC patients harboring HER2 mutations or amplification, who received combination therapy of pyrotinib and apatinib. Among them, 27 patients had baseline blood samples available for analysis. Baseline blood samples (n = 27), follow-up samples after one treatment cycle (n = 13), and samples upon disease progression (n = 18) were collected. ctDNA was extracted and sequenced using a 556-gene panel. RESULTS At baseline, HER2 mutations were detected in 21 of 27 patients through ctDNA, and 19 showed consistent results between tissue and blood sample testing. Patients with TP53 and DNMT3A alterations at baseline had significantly shorter progression-free survival (PFS). Dynamic ctDNA monitoring revealed that patients without detectable HER2 mutations after one treatment cycle had longer PFS and a trend toward longer overall survival (OS) compared to those with persistent HER2 mutations. The newly emerged mutations after resistance were infrequently found in HER2, instead primarily enriched in the chromatin remodeling pathway. CONCLUSION ctDNA holds significant value in guiding the treatment of patients with HER2 mutations. Baseline TP53 and DNMT3A alterations, along with persistent HER2 mutations after initial treatment, are associated with poorer prognosis. The primary mechanism of resistance to pyrotinib and apatinib in these patients may be attributed to chromatin remodeling rather than on-target alterations.
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Affiliation(s)
- Yucheng Dong
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Guangjian Yang
- Department of Respiratory Medical Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong 250117, China
| | - Yaning Yang
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Shuyang Zhang
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Yan Wang
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.
| | - Haiyan Xu
- Department of Comprehensive Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.
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Panahizadeh R, Panahi P, Asghariazar V, Makaremi S, Noorkhajavi G, Safarzadeh E. A literature review of recent advances in gastric cancer treatment: exploring the cross-talk between targeted therapies. Cancer Cell Int 2025; 25:23. [PMID: 39856676 PMCID: PMC11762578 DOI: 10.1186/s12935-025-03655-8] [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: 06/08/2024] [Accepted: 01/17/2025] [Indexed: 01/27/2025] Open
Abstract
BACKGROUND Gastric cancer (GC) ranks fourth in global mortality rates and fifth in prevalence, making it one of the most common cancers worldwide. Recent clinical studies have highlighted the potential of immunotherapies as a promising approach to treating GC. This study aims to shed light on the most impactful therapeutic strategies in the context of GC immunotherapy, highlighting both established and emerging approaches. MAIN BODY This review examines over 160 clinical studies conducted globally, focusing on the effectiveness of various immunotherapy modalities, including cancer vaccines, adoptive cell therapy, immune checkpoint inhibitors (ICIs), and monoclonal antibodies (mAbs). A comprehensive search of peer-reviewed literature was performed using databases such as Web of Science, PubMed, and Scopus. The selection criteria included peer-reviewed articles published primarily within the last 10 years, with a focus on studies that provided insights into targeted therapies and their mechanisms of action, clinical efficacy, and safety profiles. The findings indicate that these immunotherapy strategies can enhance treatment outcomes for GC, aligning with current treatment guidelines. ICIs like pembrolizumab and nivolumab have shown significant survival benefits in specific GC subgroups. Cancer vaccines and CAR-T cell therapies demonstrate potential, while mAbs targeting HER2 and VEGFR pathways enhance outcomes in combination regimens. We discuss the latest advancements and challenges in targeted therapy and immunotherapy for GC. Given the evolving nature of this field, this research emphasizes significant evidence-based therapies and those currently under evaluation rather than providing an exhaustive overview. Challenges include resistance mechanisms, immunosuppressive tumor environments, and inconsistent results from combination therapies. Biomarker-driven approaches and further research into emerging modalities like CAR-T cells and cancer vaccines are critical for optimizing treatments. CONCLUSIONS Immunotherapy is reshaping GC management by improving survival and quality of life. Ongoing research and clinical evaluations are crucial for refining personalized and effective therapies.
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Affiliation(s)
- Reza Panahizadeh
- Cancer Immunology and Immunotherapy Research Center, Ardabil University of Medical Sciences, Ardabil, Iran
- Students Research Committee, School of Medicine, Ardabil University of Medical Sciences, Ardabil, Iran
| | - Padideh Panahi
- Student Research Committee, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Vahid Asghariazar
- Cancer Immunology and Immunotherapy Research Center, Ardabil University of Medical Sciences, Ardabil, Iran
| | - Shima Makaremi
- Cancer Immunology and Immunotherapy Research Center, Ardabil University of Medical Sciences, Ardabil, Iran
| | - Ghasem Noorkhajavi
- Cancer Immunology and Immunotherapy Research Center, Ardabil University of Medical Sciences, Ardabil, Iran
| | - Elham Safarzadeh
- Cancer Immunology and Immunotherapy Research Center, Ardabil University of Medical Sciences, Ardabil, Iran.
- Department of Microbiology, Parasitology and Immunology, School of Medicine, Ardabil University of Medical Sciences, Ardabil, 85991-56189, Iran.
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Gao X, Guo X, Yuan W, Jiang S, Lu Z, Luo Q, Zha Y, Wang L, Li S, Wang K, Zhu X, Yao Y. Pyrotinib induces cell death in HER2-positive breast cancer via triggering HSP90-dependent HER2 degradation and ROS/HSF-1-dependent oxidative DNA damage. Cell Stress Chaperones 2024; 29:777-791. [PMID: 39566595 DOI: 10.1016/j.cstres.2024.11.004] [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: 09/03/2024] [Revised: 11/14/2024] [Accepted: 11/14/2024] [Indexed: 11/22/2024] Open
Abstract
HER2-positive breast cancer (HER2+ BC) is distinguished by its poor prognosis, propensity for early onset, and high risk of recurrence and metastasis. Consequently, anti-HER2-targeted therapy has emerged as a principal strategy in the treatment of this form of breast cancer. Pyrotinib, a novel irreversible pan-HER2 tyrosine kinase inhibitor, has brought fresh hope to patients with advanced HER2+ breast cancer. In this study, we conducted a comprehensive exploration of pyrotinib's antitumor mechanism. The in vitro results showed that pyrotinib significantly inhibited SKBR3 cells viability and induced apoptosis by promoting HER2 endocytosis and ubiquitylation, leading to HER2 degradation through the displacement of HSP90 from HER2. Beyond targeting the HER2 signaling pathway, pyrotinib also induced DNA damage, which was mediated by the activation of the reactive oxygen species/heat shock factor 1 signaling pathway and the downregulation of proliferating cell nuclear antigen expression. Furthermore, the in vivo results demonstrated a pronounced anticancer effect of pyrotinib in the SKBR3 xenograft mouse model, concomitant with a reduction in HER2 expression. In summary, our findings provide novel insights into the mechanism of pyrotinib in the treatment of HER2+ BC.
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Affiliation(s)
- Xiaomin Gao
- Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu Province, China; Department of Pharmacy, Affiliated Women's Hospital of Jiangnan University, Wuxi Maternity and Child Health Care Hospital, Wuxi, Jiangsu Province, China
| | - Xu Guo
- Department of Pharmacy, Affiliated Women's Hospital of Jiangnan University, Wuxi Maternity and Child Health Care Hospital, Wuxi, Jiangsu Province, China; Department of Pharmacy, Wuxi Maternal and Child Health Hospital Affiliated to Nanjing Medical University, Wuxi, Jiangsu Province, China
| | - Wenbo Yuan
- Department of Pharmacy, Affiliated Women's Hospital of Jiangnan University, Wuxi Maternity and Child Health Care Hospital, Wuxi, Jiangsu Province, China
| | - Sunmin Jiang
- Department of Pharmacy, Affiliated Women's Hospital of Jiangnan University, Wuxi Maternity and Child Health Care Hospital, Wuxi, Jiangsu Province, China
| | - Zihong Lu
- Department of Pharmacy, Affiliated Women's Hospital of Jiangnan University, Wuxi Maternity and Child Health Care Hospital, Wuxi, Jiangsu Province, China
| | - Qing Luo
- Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu Province, China
| | - Yuan Zha
- Department of Pharmacy, Affiliated Women's Hospital of Jiangnan University, Wuxi Maternity and Child Health Care Hospital, Wuxi, Jiangsu Province, China; Nanjing Medical University, Wuxi Medical Center, Wuxi, Jiangsu Province, China
| | - Ling Wang
- NHC Key Laboratory of Nuclear Medicine, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, Jiangsu Province, China; Department of Radiopharmaceuticals, School of Pharmacy, Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Shu Li
- Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu Province, China
| | - Ke Wang
- NHC Key Laboratory of Nuclear Medicine, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, Jiangsu Province, China; Department of Radiopharmaceuticals, School of Pharmacy, Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Xue Zhu
- NHC Key Laboratory of Nuclear Medicine, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, Jiangsu Province, China; Department of Radiopharmaceuticals, School of Pharmacy, Nanjing Medical University, Nanjing, Jiangsu Province, China.
| | - Ying Yao
- Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu Province, China; Department of Pharmacy, Affiliated Women's Hospital of Jiangnan University, Wuxi Maternity and Child Health Care Hospital, Wuxi, Jiangsu Province, China.
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Kong Y, Dong Q, Jin P, Li MY, Ma L, Yi QJ, Miao YE, Liu HY, Liu JG. Inetetamab combined with S-1 and oxaliplatin as first-line treatment for human epidermal growth factor receptor 2-positive gastric cancer. World J Gastroenterol 2024; 30:4367-4375. [PMID: 39494102 PMCID: PMC11525863 DOI: 10.3748/wjg.v30.i40.4367] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2024] [Revised: 09/07/2024] [Accepted: 09/23/2024] [Indexed: 10/16/2024] Open
Abstract
BACKGROUND Patients with human epidermal growth factor receptor 2 (HER2)-positive advanced gastric cancer have poor outcomes. Trastuzumab combined with chemotherapy is the first-line standard treatment for HER2-positive advanced gastric cancer. Inetetamab is a novel anti-HER2 drug, and its efficacy and safety in gastric cancer have not yet been reported. AIM To evaluate the efficacy and safety of the S-1 plus oxaliplatin (SOX) regimen combined with inetetamab as a first-line treatment for HER2-positive advanced gastric cancer. METHODS Thirty-eight patients with HER2-positive advanced gastric cancer or gastroesophageal junction adenocarcinoma were randomly divided into two groups: One group received inetetamab combined with the SOX regimen, and the other group received trastuzumab combined with the SOX regimen. After 4-6 cycles, patients with stable disease received maintenance therapy. The primary endpoints were progression-free survival (PFS) and overall survival (OS), and the secondary endpoints were the objective response rate, disease control rate, and adverse events (AEs). RESULTS Thirty-seven patients completed the trial, with 18 patients in the inetetamab group and 19 patients in the trastuzumab group. In the inetetamab group, the median PFS was 8.5 months, whereas it was 7.3 months in the trastuzumab group (P = 0.046); this difference was significant. The median OS in the inetetamab group vs the trastuzumab group was 15.4 months vs 14.3 months (P = 0. 33), and the objective response rate was 50% vs 42% (P = 0.63), respectively; these differences were not significant. Common AEs included leukopenia, thrombocytopenia, nausea, and vomiting. The incidence rates of grade ≥ 3 AEs were 56% in the inetetamab group and 47% in the trastuzumab group (P = 0.63), with no significant difference. CONCLUSION In the first-line treatment of HER2-positive advanced gastric cancer, inetetamab and trastuzumab showed comparable efficacy. The inetetamab group showed superior PFS, and both groups had good safety.
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Affiliation(s)
- Ying Kong
- Department of Oncology, The Second Affiliated Hospital of Shandong First Medical University, Tai’an 271000, Shandong Province, China
| | - Qi Dong
- Department of Oncology, The Second Affiliated Hospital of Shandong First Medical University, Tai’an 271000, Shandong Province, China
| | - Peng Jin
- Department of Oncology, The Second Affiliated Hospital of Shandong First Medical University, Tai’an 271000, Shandong Province, China
| | - Ming-Yan Li
- Department of Oncology, The Second Affiliated Hospital of Shandong First Medical University, Tai’an 271000, Shandong Province, China
| | - Li Ma
- Department of Oncology, The Second Affiliated Hospital of Shandong First Medical University, Tai’an 271000, Shandong Province, China
| | - Qi-Jun Yi
- Department of Oncology, The Second Affiliated Hospital of Shandong First Medical University, Tai’an 271000, Shandong Province, China
| | - Yu-E Miao
- Department of Oncology, The Second Affiliated Hospital of Shandong First Medical University, Tai’an 271000, Shandong Province, China
| | - Hai-Yan Liu
- Department of Oncology, The Second Affiliated Hospital of Shandong First Medical University, Tai’an 271000, Shandong Province, China
| | - Jian-Gang Liu
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Shandong First Medical University, Tai’an 271000, Shandong Province, China
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Li XQ, Yang J, Liu B, Han SM. Disitamab vedotin combined with apatinib in gastric cancer: A case report and review of literature. World J Clin Oncol 2024; 15:1351-1358. [DOI: 10.5306/wjco.v15.i10.1351] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2024] [Revised: 08/18/2024] [Accepted: 08/29/2024] [Indexed: 09/29/2024] Open
Abstract
BACKGROUND In patients with human epidermal growth factor receptor 2 (HER2)-overexpressing gastric cancer (GC), the combination of HER2 targeting and a standard first-line chemotherapy regimen has been demonstrated to significantly improve their prognosis. However, in a proportion of patients, cancer progresses within a short period of time, and there is currently no standard treatment after disease progression.
CASE SUMMARY This study presents a case of a 51-year-old male with advanced GC who underwent radical resection (Billroth type II subtotal gastrectomy and gastrojejunostomy) and resection of liver metastases. Immunohistochemical staining revealed a HER2 score of 2+, a dMMR status, and a Ki67 proliferation index of 30% to 40%. The gene test results indicated the presence of ERBB2 amplification and a PD-L1 expression level of less than 5%. Since December 2021, the patient has experienced disease progression during both first-line (two cycles of KN026 combined with KN046) and second-line (five cycles of nivolumab combined with trastuzumab and SOX chemotherapy) treatment regimens. The patient's prognosis following the first and second lines of treatment was unfavorable, with progression occurring in a relatively short time. For third-line therapy, disitamab vedotin (RC48) plus apatinib was used. At the time of this report, the patient had achieved a progression-free survival (PFS) of 25.8 months, which exceeded the median survival time for patients with advanced GC.
CONCLUSION Despite the unfavorable prognosis associated with advanced GC, the implementation of personalized treatment approaches may still prove beneficial for select patients. In patients with HER2-positive GC with extensive metastatic involvement, the use of the HER2-targeted combination with apatinib has demonstrated the potential to prolong both PFS and overall survival.
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Affiliation(s)
- Xiao-Qian Li
- Department of Medical Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan 510000, Shandong Province, China
| | - Jing Yang
- Department of Medical Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan 510000, Shandong Province, China
| | - Bo Liu
- Department of Medical Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan 510000, Shandong Province, China
| | - Shu-Mei Han
- Department of Medical Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan 510000, Shandong Province, China
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Yoon J, Oh DY. HER2-targeted therapies beyond breast cancer - an update. Nat Rev Clin Oncol 2024; 21:675-700. [PMID: 39039196 DOI: 10.1038/s41571-024-00924-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/28/2024] [Indexed: 07/24/2024]
Abstract
The receptor tyrosine-kinase HER2 (also known as ErbB2) is a well-established therapeutic target in patients with breast or gastric cancer selected on the basis of HER2 overexpression on immunohistochemistry and/or ERBB2 amplification on in situ hybridization. With advances in cancer molecular profiling and increased implementation of precision medicine approaches into oncology practice, actionable HER2 alterations in solid tumours have expanded to include ERBB2 mutations in addition to traditional HER2 overexpression and ERBB2 amplification. These various HER2 alterations can be found in solid tumour types beyond breast and gastric cancer, although few HER2-targeted therapeutic options have been established for the other tumour types. Nevertheless, during the 5 years since our previous Review on this topic was published in this journal, obvious and fruitful progress in the development of HER2-targeted therapies has been made, including new disease indications, innovative drugs with diverse mechanisms of action and novel frameworks for approval by regulatory authorities. These advances have culminated in the recent histology-agnostic approval of the anti-HER2 antibody-drug conjugate trastuzumab deruxtecan for patients with HER2-overexpressing solid tumours. In this new Review, we provide an update on the current development landscape of HER2-targeted therapies beyond breast cancer, as well as anticipated future HER2-directed treatment strategies to overcome resistance and thereby improve efficacy and patient outcomes.
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Affiliation(s)
- Jeesun Yoon
- Division of Medical Oncology, Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea
| | - Do-Youn Oh
- Division of Medical Oncology, Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea.
- Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.
- Integrated Major in Innovative Medical Science, Seoul National University Graduate School, Seoul, Republic of Korea.
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Huang J, Sun S, Tan Q, Zheng F, Zhou D, Man X, Hu Y, Li W, Song L, Zhang B, Xu L, Wang X, Xie X, Li H. Effectiveness and Safety of Pyrotinib-Based Therapy in the Treatment of HER2-Positive Breast Cancer Patients with Brain Metastases: A Multicenter Real-World Study. Clin Breast Cancer 2024; 24:e509-e518.e1. [PMID: 38729821 DOI: 10.1016/j.clbc.2024.04.001] [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: 08/08/2023] [Revised: 03/31/2024] [Accepted: 04/02/2024] [Indexed: 05/12/2024]
Abstract
BACKGROUND Approximately 30% to 50% of patients with human epidermal growth factor receptor 2-positive metastatic breast cancer develop brain metastasis (BMs). Pyrotinib has shown promising efficacy in these patients. However, real-world evidence supporting its use is scarce. Therefore, we evaluate the efficacy and safety of pyrotinib-based regimens in the real world. MATERIALS AND METHODS We enrolled patients with BMs from various healthcare facilities in China's Shandong region and used an updated breast-graded prognostic assessment (breast-GPA) to predict survival outcomes. RESULTS Efficacy and toxicity were assessed in 101 patients. Overall, the median progression-free survival (PFS) was 11.0 months (95% CI, 7.6-14.4 months). PFS was shorter in patients with a breast-GPA of 0 to 2.0 (P< .001). Previous treatment with pertuzumab plus trastuzumab (P = .039) and varying numbers of BMs (P = .028) had a significant positive correlation with PFS. Additionally, radiotherapy (P = .033) for BMs, especially pyrotinib concurrent with radiotherapy (P = .013), significantly prolonged the PFS. In patients with a breast-GPA of 0 to 2.0, a significant difference in PFS was observed depending on whether the brain was the first metastatic site (P< .001). Furthermore, a breast-GPA (0-2.0 vs. 2.5-4.0), and radiotherapy for BMs were found to be independent predictors of PFS. Overall, the objective response rate was 42.6%, while the disease control rate was 88.1%. Diarrhea emerged as the most common adverse event. CONCLUSION Pyrotinib-based therapy is effective and tolerable in human epidermal growth factor receptor 2-positive metastatic breast cancer with BMs. Patients who underwent radiotherapy for BMs, particularly those who received pyrotinib concurrently with radiotherapy, exhibited a more favorable prognosis.
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Affiliation(s)
- Jie Huang
- Department of Breast Medical Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250017, China
| | - Shujuan Sun
- Department of Breast Medical Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250017, China
| | - Qiaorui Tan
- Department of Breast Medical Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250017, China
| | - Fangchao Zheng
- Department of Breast Medical Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250017, China
| | - Dongdong Zhou
- Department of Breast Medical Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250017, China
| | - Xiaochu Man
- Department of Breast Medical Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250017, China
| | - Yu Hu
- Department of Medical Oncology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250012, China
| | - Wenhuan Li
- Department of Chemotherapy, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, China
| | - Lihua Song
- Department of Breast Medical Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250017, China
| | - Baoxuan Zhang
- Department of Breast Medical Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250017, China
| | - Liang Xu
- Department of Breast Medical Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250017, China
| | - Xinzhao Wang
- Department of Breast Medical Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250017, China
| | | | - Huihui Li
- Department of Breast Medical Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250017, China.
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Malla RR, Nellipudi HR, Srilatha M, Nagaraju GP. HER-2 positive gastric cancer: Current targeted treatments. Int J Biol Macromol 2024; 274:133247. [PMID: 38906351 DOI: 10.1016/j.ijbiomac.2024.133247] [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: 01/03/2024] [Revised: 06/09/2024] [Accepted: 06/16/2024] [Indexed: 06/23/2024]
Abstract
Gastric cancer (GC) is highly metastatic and characterized by HER2 amplification. Aberrant HER2 expression drives metastasis, therapy resistance, and tumor recurrence. HER2 amplification contributes to drug resistance by upregulating DNA repair enzymes and drug afflux proteins, reducing drug efficacy. HER2 modulates transcription factors critical for cancer stem cell properties, further impacting drug resistance. HER2 activity is influenced by HER-family ligands, promoting oncogenic signaling. These features point to HER2 as a targetable driver in GC. This review outlines recent advances in HER2-mediated mechanisms and their upstream and downstream signaling pathways in GC. Additionally, it discusses preclinical research investigation that comprehends trastuzumab-sensitizing phytochemicals, chemotherapeutics, and nanoparticles as adjunct therapies. These developments hold promise for improving outcomes and enhancing the management of HER2-positive GC.
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Affiliation(s)
- Rama Rao Malla
- Cancer Biology Laboratory, Department of Biochemistry and Bioinformatics, Institute of Science, Gandhi Institute of Technology and Management (Deemed to be University), Visakhapatnam, AP 530045, India
| | | | - Mundla Srilatha
- Department of Biotechnology, Sri Venkateswara University, Tirupati 517502, AP, India
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Lu D, Yuan L, Ma X, Meng F, Xu D, Jia S, Wang Z, Li Y, Zhang Z, Nan Y. The mechanism of polyphyllin in the treatment of gastric cancer was verified based on network pharmacology and experimental validation. Heliyon 2024; 10:e31452. [PMID: 38831826 PMCID: PMC11145480 DOI: 10.1016/j.heliyon.2024.e31452] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2024] [Revised: 05/15/2024] [Accepted: 05/16/2024] [Indexed: 06/05/2024] Open
Abstract
Background Polyphyllin is a class of saponins extracted from Paris polyphylla rhizomes and has been used in clinical application in China for more than 2000 years. However, the mechanism for treating gastric cancer (GC) is still unclear. This study was designed to predict the targets and mechanisms of total Polyphyllin from Paris polyphylla rhizomes for the treatment of GC. Method Firstly, PubChem and Swiss Target Prediction databases were utilized to collect the 12 ingredients of total Polyphyllin from Paris polyphylla rhizomes and their targets. GC-related genes were obtained from the GEO database. Then the intersecting targets to all these molecules that identified using Venny. Secondly, the intersecting targets were imported into STRING platform for protein-protein interaction (PPI) network. Moreover, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were conducted in DAVID website. In addition, the GEPIA was applied to perform the expression levels, transcript levels, staging, and overall survival of hub genes. In addition, we used AutoDock Vina to evaluate binding affinity of molecular docking between key ingredients and anti-GC targets. In vitro cell experiments, we detected the cell viability of gastric cancer cells at 24, 36, and 48 h using CCK-8 assay. The G0/G1 of cell cycle and apoptosis were detected by flow cytometry. Finally, quantitative real time polymerase chain reaction (qRT-PCR) was used to detect the level of hub genes, and Western blot was used to detect the changes of PI3K/Akt signal pathway. Results Firstly, we identified 12 ingredients and 286 targets of total Polyphyllin. A total of 2653 GC-related differentially expressed genes (DEGs) were collected, including 1366 up-regulated genes and 1287 down-regulated genes. Moreover, 45 targets were obtained after intersection. Secondly, results of the GO enrichment suggested that these genes were closely related to cell proliferation, migration and aging. KEGG analysis suggested that Polyphyllin in GC therapy were mostly regulated by multiple pathways, including the pathways in cancer, calcium signaling pathway, Rap1 signaling pathway, phospholipase D signaling pathway, etc. In addition, GEPIA results exhibited that PDGFRB, KIT, FGF1, GLI1, F2R, and HIF1A were associated with GC progression, stage, and survival. Besides, the molecular docking results further confirmed that the binding energy of Polyphyllin Ⅲ with HIF1A was minimal. In vitro cell experiments, Polyphyllin Ⅲ inhibited the cell viability of gastric cancer cells, blocked the cell cycle G0/G1 phase, and induced cell apoptosis. In addition, Polyphyllin Ⅲ down-regulated the mRNA levels of PDGFRB, KIT, FGF1, GLI1, F2R, and HIF1A, and regulated the PI3K/Akt signal pathway. Conclusions The results revealed that total Polyphyllin treated GC through multiple targets, multiple channels, and multiple pathways. In addition, Polyphyllin Ⅲ played an anti-gastric cancer role by inhibiting the proliferation of gastric cancer.
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Affiliation(s)
- Doudou Lu
- School of Clinical Medicine, Ningxia Medical University, Yinchuan 750004, Ningxia, China
| | - Ling Yuan
- College of Pharmacy, Ningxia Medical University, Yinchuan 750004, Ningxia, China
| | - Xiaoyan Ma
- The Affiliated TCM Hospital of Ningxia Medical University, Wuzhong 751100, Ningxia, China
| | - Fandi Meng
- Traditional Chinese Medicine College, Ningxia Medical University, Yinchuan, 750004, Ningxia, China
| | - Duojie Xu
- Traditional Chinese Medicine College, Ningxia Medical University, Yinchuan, 750004, Ningxia, China
| | - Shumin Jia
- Traditional Chinese Medicine College, Ningxia Medical University, Yinchuan, 750004, Ningxia, China
| | - Zhaozhao Wang
- Traditional Chinese Medicine College, Ningxia Medical University, Yinchuan, 750004, Ningxia, China
| | - Yahong Li
- Traditional Chinese Medicine College, Ningxia Medical University, Yinchuan, 750004, Ningxia, China
| | - Zhe Zhang
- Department of Chinese Medical Gastrointestinal, China-Japan Friendship Hospital, Beijing 100029, China
| | - Yi Nan
- Traditional Chinese Medicine College, Ningxia Medical University, Yinchuan, 750004, Ningxia, China
- Key Laboratory of Hui Ethnic Medicine Modernization of Ministry of Education, Ningxia Medical University, Yinchuan 750004, Ningxia, China
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Liu J, Zhu T, Zhao R, Ren W, Zhao F, Liu J. Elucidating molecular mechanisms and therapeutic synergy: irreversible HER2-TKI plus T-Dxd for enhanced anti-HER2 treatment of gastric cancer. Gastric Cancer 2024; 27:495-505. [PMID: 38386239 PMCID: PMC11016512 DOI: 10.1007/s10120-024-01478-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2023] [Accepted: 02/01/2024] [Indexed: 02/23/2024]
Abstract
BACKGROUND HER2-targeted therapies have improved the outcomes of HER2-positive gastric cancer (GC), yet resistance remains a challenge. We sought to explore the effects of reversible and irreversible HER2 tyrosine kinase inhibitors (TKIs) alone or in combination with the HER2-targeting antibody drug conjugate trastuzumab deruxtecan (T-Dxd). METHODS The effects of HER2-TKIs on HER2 and downstream signaling were evaluated via Western blotting. Proteasomal inhibitors and co-immunoprecipitation assays were performed to explore the role of proteasomal degradation in HER2 expression modulation, and immunofluorescence assays were employed to explore mechanisms of HER2 internalization. The synergistic potential of the irreversible HER2-TKI pyrotinib in combination with T-Dxd was validated using growth and viability assays in anti-HER2-positive GC cell cultures and tumor growth and immunohistochemical staining assays in a mouse xenograft model. RESULTS Our study revealed that reversible HER2-TKIs elevated HER2 protein levels, whereas irreversible HER2-TKIs decreased them. Pyrotinib triggered HER2 degradation within the proteasome by promoting ubiquitination and dissociation from HSP90. Furthermore, pyrotinib substantially induced HER2 internalization, which led to improved cellular uptake of T-Dxd. The increased T-Dxd uptake was accompanied by greater efficacy in suppressing the growth of GC cells and enhanced anti-tumor effects in an animal model. CONCLUSION In summary, our research reveals the molecular mechanisms of irreversible HER2-TKIs in regulating HER2 protein expression by promoting HER2 internalization. These findings advance our comprehension of targeted therapy for GC and provide a promising therapeutic combination strategy with enhanced efficacy against HER2-positive GC.
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Affiliation(s)
- Jiankun Liu
- Department of Oncology, Hebei Medical University, Shijiazhuang, 050017, Hebei, China
| | - Tienian Zhu
- Department of Oncology, Hebei Medical University, Shijiazhuang, 050017, Hebei, China.
- Department of Medical Oncology, Bethune International Peace Hospital, Shijiazhuang, 050082, Hebei, China.
| | - Ruijing Zhao
- Department of Immunology, Hebei Medical University, Key Laboratory of Immune Mechanism and Intervention On Serious Disease in Hebei Province, Shijiazhuang, 050017, Hebei, China
| | - Wenjun Ren
- Department of Oncology, Hebei Medical University, Shijiazhuang, 050017, Hebei, China
| | - Fei Zhao
- Department of Oncology, Hebei Medical University, Shijiazhuang, 050017, Hebei, China
| | - Jingpu Liu
- Department of Medical Oncology, Bethune International Peace Hospital, Shijiazhuang, 050082, Hebei, China
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Kashani SF, Abedini Z, Darehshouri AF, Jazi K, Bereimipour A, Malekraeisi MA, Javanshir HT, Mahmoodzadeh H, Hadjilooei F. Investigation of Molecular Mechanisms of S-1, Docetaxel and Cisplatin in Gastric Cancer with a History of Helicobacter Pylori Infection. Mol Biotechnol 2024; 66:1303-1313. [PMID: 38273052 DOI: 10.1007/s12033-023-01032-2] [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: 03/25/2023] [Accepted: 12/12/2023] [Indexed: 01/27/2024]
Abstract
Gastric cancer rates and fatality rates have not decreased. Gastric cancer treatment has historically included surgery (both endoscopic and open), chemotherapy, targeted therapy, and immunotherapy. One of the aggravating carriers of this cancer is Helicobacter pylori infection. Various drug combinations are used to treat gastric cancer. However, examining the molecular function of these drugs, depending on whether or not there is a history of Helicobacter pylori infection, can be a better help in the treatment of these patients. This study was designed as bioinformatics. Various datasets such as patients with gastric cancer, with and without a history of H. pylori, and chemotherapy drugs cisplatin, docetaxel, and S-1 were selected. Using Venn diagrams, the similarities between gene expression profiles were assessed and isolated. Then, selected the signal pathways, ontology of candidate genes and proteins. Then, in clinical databases, we confirmed the candidate genes and proteins. The association between gastric cancer patients with and without a history of H. pylori with chemotherapy drugs was investigated. The pathways of cellular aging, apoptosis, MAPK, and TGFβ were clearly seen. After a closer look at the ontology of genes and the relationship between proteins, we nominated important biomolecules. Accordingly, NCOR1, KIT, MITF, ESF1, ARNT2, TCF7L2, and KRR1 proteins showed an important role in these connections. Finally, NCOR1, KIT, KRR1, and ESF1 proteins showed a more prominent role in the molecular mechanisms of S-1, Docetaxel, and Cisplatin in gastric cancer associated with or without H. pylori.
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Affiliation(s)
| | - Zainab Abedini
- Medical Genomics Research Center, Tehran Medical Sciences Islamic Azad University, Tehran, Iran
| | | | - Kimia Jazi
- Student Research Committee, Faculty of Medicine, Medical University of Qom, Qom, Iran
| | - Ahmad Bereimipour
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran.
- Department of Biological Sciences and BioDiscovery Institute, University of North Texas, Denton, TX, 76203, USA.
| | | | | | | | - Farimah Hadjilooei
- Cancer Research Center, Tehran University of Medical Sciences, Tehran, Iran
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Jiang K, Hong R, Xia W, Lu Q, Li L, Huang J, Shi Y, Yuan Z, Zheng Q, An X, Xue C, Huang J, Bi X, Chen M, Zhang J, Xu F, Wang S. Pyrotinib Combined with Vinorelbine in Patients with Previously Treated HER2-Positive Metastatic Breast Cancer: A Multicenter, Single-Arm, Prospective Study. Cancer Res Treat 2024; 56:513-521. [PMID: 37846468 PMCID: PMC11016657 DOI: 10.4143/crt.2023.786] [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: 06/25/2023] [Accepted: 10/10/2023] [Indexed: 10/18/2023] Open
Abstract
PURPOSE This study aims to evaluate the efficacy and safety of a new combination treatment of vinorelbine and pyrotinib in human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) and provide higher level evidence for clinical practice. MATERIALS AND METHODS This was a prospective, single-arm, phase 2 trial conducted at three institutions in China. Patients with HER2-positive MBC, who had previously been treated with trastuzumab plus a taxane or trastuzumab plus pertuzumab combined with a chemotherapeutic agent, were enrolled between March 2020 and December 2021. All patients received pyrotinib 400 mg orally once daily plus vinorelbine 25 mg/m2 intravenously or 60-80 mg/m2 orally on day 1 and day 8 of 21-day cycle. The primary endpoint was progression-free survival (PFS), and the secondary endpoints included the objective response rate (ORR), disease control rate (DCR), overall survival, and safety. RESULTS A total of 39 patients were enrolled. All patients had been pretreated with trastuzumab and 23.1% (n=9) of them had accepted trastuzumab plus pertuzumab. The median follow-up time was 16.3 months (95% confidence interval [CI], 5.3 to 27.2), and the median PFS was 6.4 months (95% CI, 4.0 to 8.8). The ORR was 43.6% (95% CI, 27.8% to 60.4%) and the DCR was 84.6% (95% CI, 69.5% to 94.1%). The median PFS of patients with versus without prior pertuzumab treatment was 4.6 and 8.3 months (p=0.017). The most common grade 3/4 adverse events were diarrhea (28.2%), neutrophil count decreased (15.4%), white blood cell count decreased (7.7%), vomiting (5.1%), and anemia (2.6%). CONCLUSION Pyrotinib plus vinorelbine showed promising efficacy and tolerable toxicity as second-line treatment in patients with HER2-positive MBC.
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Affiliation(s)
- Kuikui Jiang
- Department of Medical Oncology, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Ruoxi Hong
- Department of Medical Oncology, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Wen Xia
- Department of Medical Oncology, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Qianyi Lu
- Department of Radiology, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Liang Li
- Department of Medical Oncology, Meizhou People's Hospital (Huangtang Hospital), Meizhou, China
| | - Jianhao Huang
- Department of Oncology Surgery, Shantou Central Hospital, Shantou, China
| | - Yanxia Shi
- Department of Medical Oncology, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Zhongyu Yuan
- Department of Medical Oncology, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Qiufan Zheng
- Department of Medical Oncology, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Xin An
- Department of Medical Oncology, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Cong Xue
- Department of Medical Oncology, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Jiajia Huang
- Department of Medical Oncology, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Xiwen Bi
- Department of Medical Oncology, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Meiting Chen
- Department of Medical Oncology, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Jingmin Zhang
- Department of Medical Oncology, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Fei Xu
- Department of Medical Oncology, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Shusen Wang
- Department of Medical Oncology, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, China
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15
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Liu X, Zhang X, Shao Z, Zhong X, Ding X, Wu L, Chen J, He P, Cheng Y, Zhu K, Zheng D, Jing J, Luo T. Pyrotinib and chrysin synergistically potentiate autophagy in HER2-positive breast cancer. Signal Transduct Target Ther 2023; 8:463. [PMID: 38110365 PMCID: PMC10728098 DOI: 10.1038/s41392-023-01689-w] [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: 02/10/2023] [Revised: 06/05/2023] [Accepted: 09/03/2023] [Indexed: 12/20/2023] Open
Abstract
Human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC) has been the most challenging subtype of BC, consisting of 20% of BC with an apparent correlation with poor prognosis. Despite that pyrotinib, a new HER2 inhibitor, has led to dramatic improvements in prognosis, the efficacy of pyrotinib monotherapy remains largely restricted due to its acquired resistance. Therefore, identifying a new potential antitumor drug in combination with pyrotinib to amplify therapeutic efficacy is a pressing necessity. Here, we reported a novel combination of pyrotinib with chrysin and explored its antitumor efficacy and the underlying mechanism in HER2-positive BC. We determined that pyrotinib combined with chrysin yielded a potent synergistic effect to induce more evident cell cycle arrest, inhibit the proliferation of BT-474 and SK-BR-3 BC cells, and repress in vivo tumor growth in xenograft mice models. This may be attributed to enhanced autophagy induced by endoplasmic reticulum stress. Furthermore, the combined treatment of pyrotinib and chrysin induced ubiquitination and glucose-6-phosphate dehydrogenase (G6PD) degradation by upregulating zinc finger and BTB/POZ domain-containing family protein 16 (ZBTB16) in tumorigenesis of BC. Mechanistically, we identified that miR-16-5p was a potential upstream regulator of ZBTB16, and it showed a significant inverse correlation with ZBTB16. Inhibition of miR-16-5p overexpression by restoring ZBTB16 significantly potentiated the overall antitumor efficacy of pyrotinib combined with chrysin against HER2-positive BC. Together, these findings demonstrate that the combined treatment of pyrotinib and chrysin enhances autophagy in HER2-positive BC through an unrecognized miR-16-5p/ZBTB16/G6PD axis.
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Affiliation(s)
- Xiaoxiao Liu
- Institute for Breast Health Medicine, Cancer Center, Breast Center, West China Hospital, Sichuan University, 610041, Chengdu, Sichuan, China
- Department of Radiation Oncology, Cancer Center, Affiliated Hospital of Xuzhou Medical University; Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Xuzhou Medical University, 221000, Xuzhou, China
| | - Xing Zhang
- Department of Orthopedics, Trauma and Reconstructive Surgery, University Hospital RWTH Aachen, Aachen, 52074, Germany
| | - Zhiying Shao
- Cancer Institute, Xuzhou Medical University, 221000, Xuzhou, Jiangsu, China
| | - Xiaorong Zhong
- Institute for Breast Health Medicine, Cancer Center, Breast Center, West China Hospital, Sichuan University, 610041, Chengdu, Sichuan, China
| | - Xin Ding
- Department of Radiation Oncology, Cancer Center, Affiliated Hospital of Xuzhou Medical University; Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Xuzhou Medical University, 221000, Xuzhou, China
| | - Liang Wu
- Division of Nephrology and Transplantation, Department of Internal Medicine, University Medical Center Rotterdam Erasmus MC, Rotterdam, 3015 GD, The Netherlands
| | - Jie Chen
- Institute for Breast Health Medicine, Department of General Surgery, Breast Center, West China Hospital, Sichuan University, 610041, Chengdu, Sichuan, China
| | - Ping He
- Institute for Breast Health Medicine, Cancer Center, Breast Center, West China Hospital, Sichuan University, 610041, Chengdu, Sichuan, China
| | - Yan Cheng
- Institute for Breast Health Medicine, Cancer Center, Breast Center, West China Hospital, Sichuan University, 610041, Chengdu, Sichuan, China
| | - Kunrui Zhu
- Institute for Breast Health Medicine, Cancer Center, Breast Center, West China Hospital, Sichuan University, 610041, Chengdu, Sichuan, China
| | - Dan Zheng
- Institute for Breast Health Medicine, Cancer Center, Breast Center, West China Hospital, Sichuan University, 610041, Chengdu, Sichuan, China
| | - Jing Jing
- Institute for Breast Health Medicine, West China Hospital, Sichuan University, 610041, Chengdu, Sichuan, China.
| | - Ting Luo
- Institute for Breast Health Medicine, Cancer Center, Breast Center, West China Hospital, Sichuan University, 610041, Chengdu, Sichuan, China.
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Bu X, Liu Y, Wang L, Yan Z, Xin G, Su W. Oct4 promoted proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) in colon cancer cells by activating the SCF/c-Kit signaling pathway. Cell Cycle 2023; 22:291-302. [PMID: 36258646 PMCID: PMC9851249 DOI: 10.1080/15384101.2022.2112486] [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: 06/30/2022] [Revised: 08/08/2022] [Accepted: 08/09/2022] [Indexed: 01/27/2023] Open
Abstract
Octamer-binding transcription factor 4 (Oct4) is closely related to the occurrence and development of cancer. In the present study, we paid a special interest in exploring the effect of Oct4 on colon cancer (CC) proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) and its molecular mechanism. Immunohistochemistry (IHC) was used to detect the expression level of Oct4 in colon tissue of patients with colon cancer. Oct4 overexpression vector pcDNA-Oct4 was used to stably express Oct4 in human colon cancer cells HT29 and SW480. Cell counting kit-8 (CCK-8) assay was used to detect the cell proliferation. The invasion and migration abilities were observed by transwell and wound healing assays. The expression of EMT relate genes were observed by Western blot. We found that Oct4 was up-regulated in human colon cancer tissues than that in paracancerous tissues. The proliferation, migration, and invasion of HT29 and SW480 cells was significantly induced by transfection of pcDNA-Oct4. Furthermore, Oct4 overexpression enhanced EMT of CC cells, characterized by the increased expression of vimentin, Twist, and Snail, as well as decreased expression of E-cadherin. Mechanistically, Oct4 overexpression activated stem cell factor (SCF)/c-Kit signaling pathway in CC cells, and the SCF/c-Kit signaling inhibitor imatinib reversed pro-oncogenic effects of Oct4. These finding provide an insight into the potential of Oct4 for CC diagnosis and therapy.
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Affiliation(s)
- Xiaoqian Bu
- Department of Cancer Center, Third Hospital of Shanxi Medical University, Taiyuan, China
| | - Yulong Liu
- Department of Medical Laboratory, Shanxi Bethune Hospital, Taiyuan, China
| | - Lin Wang
- Department of Pathology, Shanxi Bethune Hospital, Taiyuan, China
| | - Zhengzheng Yan
- Department of Gastrointestinal Surgery, Shanxi Bethune Hospital, Taiyuan, China
| | - Guo Xin
- Department of Cancer Center, Third Hospital of Shanxi Medical University, Taiyuan, China
| | - Wen Su
- Department of Cancer Center, Affiliated Cancer Hospital of Shanxi Medical University, Taiyuan, China
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Single-cell analysis reveals the potential mechanisms of pyrotinib resistance in non-small cell lung cancer. Signal Transduct Target Ther 2023; 8:17. [PMID: 36635267 PMCID: PMC9837066 DOI: 10.1038/s41392-022-01226-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2022] [Revised: 09/21/2022] [Accepted: 10/11/2022] [Indexed: 01/14/2023] Open
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Wang Z, Zhang XC, Feng WN, Zhang L, Liu XQ, Guo WB, Deng YM, Zou QF, Yang JJ, Zhou Q, Wang BC, Chen HJ, Tu HY, Yan HH, Wu YL. Circulating tumor cells dynamics during chemotherapy predict survival and response in advanced non-small-cell lung cancer patients. Ther Adv Med Oncol 2023; 15:17588359231167818. [PMID: 37113733 PMCID: PMC10126699 DOI: 10.1177/17588359231167818] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Accepted: 03/17/2023] [Indexed: 04/29/2023] Open
Abstract
Background Circulating tumor cells (CTCs) are prognostic biomarker in non-small-cell lung cancer (NSCLC). CTCs could also be used as predictor of efficacy of systemic treatments in advanced NSCLC. Objectives We described the dynamic changes of CTCs during first-line platinum-based chemotherapy in advanced NSCLC and clarified the correlation between CTC counts and efficacy of chemotherapy. Design Chemotherapy is administered and blood specimens are collected at four time points from baseline to disease progression for CTC detection. Methods This multicenter prospective study enrolled patients with previously untreated stage III or IV NSCLC fit for standard platinum-based chemotherapy. Bloods were sampled as per standard operating procedures at baseline, cycle 1 and cycle 4 of chemotherapy, and at disease progression for CTC analysis using the CellSearch system. Results Among 150 patients enrolled, median overall survival (OS) was 13.8, 8.4, and 7.9 months in patients with CTC-, KIT-CTC, and KIT+CTC at baseline (p = 0.002). Patients with persistent negative CTC (46.0%) had longer progression-free survival [5.7 months, 95% confidence interval (CI): 5.0-6.5 versus 3.0 months, 0.6-5.4; hazard ratio (HR): 0.34, 95% CI: 0.18-0.67) and OS (13.1 months, 10.9-15.3 versus 5.6 months, 4.1-7.1; HR: 0.17, 0.08-0.36) compared with patients with persistent positive CTC (10.7%), which was not impacted by chemotherapy. Chemotherapy decreased CTC from 36.0% (54/150) to 13.7% (13/95). Conclusions CTC persistent presence during treatment represents poor prognosis and resistance to chemotherapy in advanced NSCLC. Chemotherapy could effectively eliminate CTCs. Molecular characterization and the functionalization of CTC will be warranted for further intensive investigation. Trial registration NCT01740804.
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Affiliation(s)
| | | | | | - Li Zhang
- Cancer Center, Sun Yat-sen University, Guangzhou, China
| | | | - Wei-Bang Guo
- Guangdong Lung Cancer Institute, Guangdong Provincial Key Laboratory of Translational Medicine in Lung Cancer, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
| | - Yan-Ming Deng
- The First People’s Hospital of Foshan, Foshan, China
| | - Qing-Feng Zou
- Affiliated Cancer Hospital of Guangzhou Medical University, Guangzhou, China
| | - Jin-Ji Yang
- Guangdong Lung Cancer Institute, Guangdong Provincial Key Laboratory of Translational Medicine in Lung Cancer, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
| | - Qing Zhou
- Guangdong Lung Cancer Institute, Guangdong Provincial Key Laboratory of Translational Medicine in Lung Cancer, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
| | - Bin-Chao Wang
- Guangdong Lung Cancer Institute, Guangdong Provincial Key Laboratory of Translational Medicine in Lung Cancer, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
| | - Hua-Jun Chen
- Guangdong Lung Cancer Institute, Guangdong Provincial Key Laboratory of Translational Medicine in Lung Cancer, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
| | - Hai-Yan Tu
- Guangdong Lung Cancer Institute, Guangdong Provincial Key Laboratory of Translational Medicine in Lung Cancer, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
| | | | - Yi-Long Wu
- Guangdong Lung Cancer Institute, Guangdong Provincial Key Laboratory of Translational Medicine in Lung Cancer, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, 106 Zhongshan Er Rd, Guangzhou 510080, China
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Chen Y, Zhang R, Mi D, Wang Q, Huang T, Dong X, Zhang H, Xiao H, Shi S. SPK1/S1P axis confers gastrointestinal stromal tumors (GISTs) resistance of imatinib. Gastric Cancer 2023; 26:26-43. [PMID: 35999321 PMCID: PMC9398498 DOI: 10.1007/s10120-022-01332-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Accepted: 08/08/2022] [Indexed: 02/07/2023]
Abstract
BACKGROUND Imatinib mesylate (IM) is highly effective in the treatment of gastrointestinal stromal tumors (GISTs). However, the most of GISTs patients develop secondary drug resistance after 1-3 years of IM treatment. The aim of this study was to explore the IM-resistance mechanism via the multi-scope combined with plasma concentration of IM, genetic polymorphisms and plasma sensitive metabolites. METHODS This study included a total of 40 GISTs patients who had been regularly treated and not treated with IM. The plasma samples were divided into three experiments, containing therapeutic drug monitoring (TDM), OCT1 genetic polymorphisms and non-targeted metabolomics. According to the data of above three experiments, the IM-resistant cell line, GIST-T1/IMR cells, was constructed for verification the IM-resistance mechanism. RESULTS The results of non-targeted metabolomics analysis suggested that the sphingophospholipid metabolic pathway including the SPK1/S1P axis was inferred in IM-insensitive patients with GISTs. A GIST cell line (GIST-T1) was immediately induced as an IM resistance cell model (GIST-T1/IMR) and we found that blocking the signal pathway of SPK1/S1P in the GIST-T1/IMR could sensitize treatment of IM and reverse the IM-resistance. CONCLUSIONS Our findings suggest that IM secondary resistance is associated with the elevation of S1P, and blockage the signaling pathway of SPK1/S1P warrants evaluation as a potential therapeutic strategy in IM-resistant GISTs. The design of this study from blood management, group information collection, IM plasma concentration with different elements, identification of sphingolipid metabolism and lastly verification the function of SPK1/S1P in the IM-resistance GISTs cells.
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Affiliation(s)
- Yan Chen
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, No.1166 Liutai Avenue, Chengdu, 611137, People's Republic of China
- Department of Clinical Pharmacy, School of Medicine, Sichuan Cancer Hospital and Institute, Sichuan Cancer Center, University of Electronic Science and Technology of China, Chengdu, 610042, People's Republic of China
| | - Rui Zhang
- Department of Clinical Pharmacy, School of Medicine, Sichuan Cancer Hospital and Institute, Sichuan Cancer Center, University of Electronic Science and Technology of China, Chengdu, 610042, People's Republic of China
| | - Dandan Mi
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, No.1166 Liutai Avenue, Chengdu, 611137, People's Republic of China
| | - Qiuju Wang
- Department of Clinical Laboratory, School of Medicine, Sichuan Cancer Hospital and Institute, Sichuan Cancer Center, University of Electronic Science and Technology of China, Chengdu, 610042, People's Republic of China
| | - Tingwenli Huang
- Department of Clinical Pharmacy, School of Medicine, Sichuan Cancer Hospital and Institute, Sichuan Cancer Center, University of Electronic Science and Technology of China, Chengdu, 610042, People's Republic of China
| | - Xinwei Dong
- Department of Clinical Pharmacy, Nantong Tumor Hospital, Nantong, 226300, People's Republic of China
| | - Hongwei Zhang
- Department of Anesthesiology, School of Medicine, Sichuan Cancer Hospital and Institute, Sichuan Cancer Center, University of Electronic Science and Technology of China, Chengdu, 610042, People's Republic of China
| | - Hongtao Xiao
- Department of Clinical Pharmacy, School of Medicine, Sichuan Cancer Hospital and Institute, Sichuan Cancer Center, University of Electronic Science and Technology of China, Chengdu, 610042, People's Republic of China
| | - Sanjun Shi
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, No.1166 Liutai Avenue, Chengdu, 611137, People's Republic of China.
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He L, Shen X, Liu Y, Gao L, Wu J, Yu C, Li G, Wang X, Shao X. The reversal of anti-HER2 resistance in advanced HER2-positive breast cancer using apatinib: two cases reports and literature review. Transl Cancer Res 2022; 11:4206-4217. [PMID: 36523304 PMCID: PMC9745359 DOI: 10.21037/tcr-22-2483] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2022] [Accepted: 11/15/2022] [Indexed: 09/29/2024]
Abstract
BACKGROUND Human epidermal growth factor receptor 2 (HER2)-targeted treatment has yielded a notable clinical benefit in patients with HER2-positive breast cancer. However, nearly 50% of patients still suffer disease progression due to resistance to HER2-targeted therapy. After the failure of macromolecular monoclonal antibodies (mAbs) therapy, we can choose small molecule tyrosine kinase inhibitors (TKIs) to reverse HER2 resistance. When small molecule TKIs resistance, we can use mAb combined with small molecule TKI, or antibody-drug conjugates (ADCs) to reverse HER2 resistance. However, then due to the availability and price of ADCs, patients may not use them. Consequently, new therapeutic approaches are required to overcome HER2-targeted therapy resistance. Vascular endothelial growth factor and its receptors (VEGF/VEGFRs) promote tumor angiogenesis. They can also activate downstream signaling pathways to promote tumorigenesis. VEGFR is a key regulator of the tyrosine kinase signaling pathway and may be a potential target in HER2-positive breast cancer. Apatinib is a small molecule TKI that specifically binds to VEGFR2 and thus exerts an antitumor effect. Although there is no definite indication for apatinib in breast cancer, it has a good benefit in advanced gastric cancer. CASE DESCRIPTION The two patients we reported were both HER2-positive breast cancer who we followed for more than 10 years. After the failure of multi-line anti-HER2 treatment, apatinib combined with anti-HER2 treatment had PFS of 8.4 months and 10.6 months, respectively. One patient had grade 2 hand-foot syndrome. The other had grade 2 leukopenia and grade 2 thrombocytopenia, both of them improved after control. And the best response of them were PR and SD, respectively. CONCLUSIONS Our cases demonstrate that, in HER2-positive breast cancer patients with HER2-targeted resistance, apatinib may be able to reverse HER2 resistance. These two cases suggest an alternative method for clinical HER2-targeted treatment of drug-resistant breast cancer patients and provide new insights for future research.
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Affiliation(s)
- Libin He
- The Second Affiliated College of Zhejiang Chinese Medical University, Hangzhou, China
| | - Xiabo Shen
- Department of Breast Medical Oncology, Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, China
- Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
| | - Yiyuan Liu
- The Second Affiliated College of Zhejiang Chinese Medical University, Hangzhou, China
| | - Lu Gao
- The Second Affiliated College of Zhejiang Chinese Medical University, Hangzhou, China
| | - Jiayi Wu
- The Second Affiliated College of Zhejiang Chinese Medical University, Hangzhou, China
| | - Chang Yu
- Department of Pathology, Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, China
| | - Guangliang Li
- Department of Breast Medical Oncology, Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, China
- Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
| | - Xiaojia Wang
- Department of Breast Medical Oncology, Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, China
- Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
| | - Xiying Shao
- Department of Breast Medical Oncology, Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, China
- Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
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Sun Y, Ma C, Li Z, Zhang J. Palladium/GF-Phos-catalyzed asymmetric carbenylative amination to access chiral pyrrolidines and piperidines. Chem Sci 2022; 13:11150-11155. [PMID: 36320471 PMCID: PMC9517724 DOI: 10.1039/d2sc03999k] [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: 07/18/2022] [Accepted: 09/01/2022] [Indexed: 11/21/2022] Open
Abstract
The cross-coupling of N-tosylhydrazones has emerged as a powerful method for the construction of structurally diverse molecules, but the development of catalytic enantioselective versions still poses considerable challenges and only very limited examples have been reported. We herein report an asymmetric palladium/GF-Phos-catalyzed carbenylative amination reaction of N-tosylhydrazones and (E)-vinyl iodides pendent with amine, which allows facile access to a range of chiral pyrrolidines and piperidines in good yields (45-93%) with up to 96.5 : 3.5 er. Moreover, mild conditions, general substrate scope, scaled-up preparation, as well as the efficient synthesis of natural product (-)-norruspoline are practical features of this method.
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Affiliation(s)
- Yue Sun
- Department of Chemistry, Fudan University 2005 Songhu Road Shanghai 200438 China
| | - Chun Ma
- Department of Chemistry, Fudan University 2005 Songhu Road Shanghai 200438 China
| | - Zhiming Li
- Department of Chemistry, Fudan University 2005 Songhu Road Shanghai 200438 China
| | - Junliang Zhang
- Department of Chemistry, Fudan University 2005 Songhu Road Shanghai 200438 China
- Zhuhai Fudan Innovation Institute Hengqing District Zhuhai 519000 China
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22
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Protein tyrosine kinase inhibitor resistance in malignant tumors: molecular mechanisms and future perspective. Signal Transduct Target Ther 2022; 7:329. [PMID: 36115852 PMCID: PMC9482625 DOI: 10.1038/s41392-022-01168-8] [Citation(s) in RCA: 114] [Impact Index Per Article: 38.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Revised: 07/08/2022] [Accepted: 08/26/2022] [Indexed: 02/07/2023] Open
Abstract
AbstractProtein tyrosine kinases (PTKs) are a class of proteins with tyrosine kinase activity that phosphorylate tyrosine residues of critical molecules in signaling pathways. Their basal function is essential for maintaining normal cell growth and differentiation. However, aberrant activation of PTKs caused by various factors can deviate cell function from the expected trajectory to an abnormal growth state, leading to carcinogenesis. Inhibiting the aberrant PTK function could inhibit tumor growth. Therefore, tyrosine kinase inhibitors (TKIs), target-specific inhibitors of PTKs, have been used in treating malignant tumors and play a significant role in targeted therapy of cancer. Currently, drug resistance is the main reason for limiting TKIs efficacy of cancer. The increasing studies indicated that tumor microenvironment, cell death resistance, tumor metabolism, epigenetic modification and abnormal metabolism of TKIs were deeply involved in tumor development and TKI resistance, besides the abnormal activation of PTK-related signaling pathways involved in gene mutations. Accordingly, it is of great significance to study the underlying mechanisms of TKIs resistance and find solutions to reverse TKIs resistance for improving TKIs efficacy of cancer. Herein, we reviewed the drug resistance mechanisms of TKIs and the potential approaches to overcome TKI resistance, aiming to provide a theoretical basis for improving the efficacy of TKIs.
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23
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Chen D, Zhong X, Lin L, Xie J, Lian Y, Xu L. Comparative efficacy and adverse reactions of apatinib-chemotherapy combinations versus chemotherapy alone for treatment of advanced colorectal cancer: a meta-analysis of randomized controlled trials. Am J Transl Res 2022; 14:6703-6711. [PMID: 36247297 PMCID: PMC9556443] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Accepted: 08/09/2022] [Indexed: 06/16/2023]
Abstract
OBJECTIVE Apatinib mesylate is the first small-molecule anti-angiogenic agent that has been shown to be effective and well-tolerated for treatment of advanced gastric cancer, and has shown encouraging efficacy for treatment of advanced colorectal cancer (CRC). However, previous studies reported diverse efficacy and safety results of apatinib for treatment of advanced CRC. This meta-analysis aimed to compare the efficacy and safety of apatinib plus chemotherapy (trial group) versus chemotherapy alone (control group) for treatment of advanced CRC. METHODS A joint search was performed in electronic databases to retrieve randomized clinical trials (RCTs) reporting the efficacy and adverse reactions of apatinib in the treatment of advanced CRC. The pooled survival, treatment responses, and safety were estimated and compared between the trial and control groups. RESULTS A total of 7 eligible RCTs involving 539 colorectal cancer patients were enrolled. Meta-analysis showed significantly higher overall response rate (risk ratio (RR) = 1.46, P < 0.00001), disease control rate (RR = 1.24, P < 0.00001), complete response (RR = 1.72, P = 0.01), PR (RR = 1.43, P = 0.001), overall survival (mean difference (MD) = 3.89, P = 0.0006), and progression-free survival (MD = 2.94, P < 0.00001) and lower progressive disease (RR = 0.37, P < 0.00001) in the trial group than in the control group; however, there were no significant differences between the two groups in terms of stable disease (RR = 0.89, P = 0.38) or incidence of adverse reactions (RR = 1.01, P = 0.92). CONCLUSION Apatinib plus chemotherapy shows a higher efficacy and comparable safety for treatment of advanced CRC in relative to chemotherapy alone.
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Affiliation(s)
- Dengsheng Chen
- Department of Pharmacy, Sanming First Hospital, Affiliated Hospital of Fujian Medical UniversitySanming 365000, Fujian Province, China
| | - Xinzhu Zhong
- Department of Pharmacy, Sanming First Hospital, Affiliated Hospital of Fujian Medical UniversitySanming 365000, Fujian Province, China
| | - Lei Lin
- Department of Pharmacy, Sanming First Hospital, Affiliated Hospital of Fujian Medical UniversitySanming 365000, Fujian Province, China
| | - Jiejie Xie
- Department of Pharmacy, Sanming First Hospital, Affiliated Hospital of Fujian Medical UniversitySanming 365000, Fujian Province, China
| | - Yubao Lian
- Department of Infectious Diseases, Sanming First Hospital, Affiliated Hospital of Fujian Medical UniversitySanming 365000, Fujian Province, China
| | - Luning Xu
- Department of Pharmacy, Sanming First Hospital, Affiliated Hospital of Fujian Medical UniversitySanming 365000, Fujian Province, China
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24
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Zhang Z, Zhang S, Lin B, Wang Q, Nie X, Shi Y. Combined treatment of marizomib and cisplatin modulates cervical cancer growth and invasion and enhances antitumor potential in vitro and in vivo. Front Oncol 2022; 12:974573. [PMID: 36110967 PMCID: PMC9468930 DOI: 10.3389/fonc.2022.974573] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Accepted: 08/08/2022] [Indexed: 11/13/2022] Open
Abstract
Proteasome inhibition is an attractive approach for anticancer therapy. Cisplatin (cis-diamminedichloroplatinum, CDDP) is widely used as a standard chemotherapy drug in the treatment of solid malignant tumors, such as cervical cancer, ovarian cancer, colorectal cancer, and lung cancer. However, the development of CDDP resistance largely limits its clinical application. Proteasome inhibitors may enhance traditional chemotherapy agent-induced cytotoxicity and apoptosis. Marizomib (NPI-0052, salinosporamide A, Mzb), a second-generation proteasome inhibitor, shows synergistic anticancer activity with some drugs. Currently, the effect of Mzb on cervical cancer cell proliferation remains unclear. In this study, we explored the role of Mzb in three cervical cancer cell lines, HeLa, CaSki, and C33A, representing major molecular subtypes of cervical cancer and xenografts. We found that Mzb alone showed noteworthy cytotoxic effects, and its combination with CDDP resulted in more obvious cytotoxicity and apoptosis in cervical cancer cell lines and xenografts. In order to investigate the mechanism of this effect, we probed whether Mzb alone or in combination with CDDP had a better antitumor response by enhancing CDDP-induced angiopoietin 1 (Ang-1) expression and inhibiting the expression of TEK receptor tyrosine kinase (Tie-2) in the Ang-1/Tie-2 pathway, FMS-like tyrosine kinase 3 ligand (Flt-3L) and stem cell factor (SCF) as identified by a cytokine antibody chip test. The results suggest that Mzb has better antitumor effects on cervical cancer cells and can sensitize cervical cancer cells to CDDP treatment both in vitro and in vivo. Accordingly, we conclude that the combination of CDDP with Mzb produces synergistic anticancer activity and that Mzb may be a potential effective drug in combination therapy for cervical cancer patients.
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Affiliation(s)
- Ziruizhuo Zhang
- Department of Pathology, School of Basic Medical Sciences, Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Songcheng Zhang
- Department of Pediatrics, Nanyang Chinese Medicine Hospital, Nanyang, Henan, China
| | - Bingjie Lin
- Department of Pathology, School of Basic Medical Sciences, Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Qixin Wang
- Department of Pathology, School of Basic Medical Sciences, Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Xiaojing Nie
- Department of Pathology, School of Basic Medical Sciences, Xinjiang Medical University, Urumqi, Xinjiang, China
- Xinjiang Key Laboratory of Molecular Biology for Endemic Diseases, Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Yonghua Shi
- Department of Pathology, School of Basic Medical Sciences, Xinjiang Medical University, Urumqi, Xinjiang, China
- Xinjiang Key Laboratory of Molecular Biology for Endemic Diseases, Xinjiang Medical University, Urumqi, Xinjiang, China
- *Correspondence: Yonghua Shi,
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25
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Yang G, Xu H, Yang Y, Zhang S, Xu F, Hao X, Li J, Xing P, Hu X, Liu Y, Wang L, Lin L, Wang Z, Duan J, Wang J, Wang Y. Pyrotinib combined with apatinib for targeting metastatic non-small cell lung cancer with HER2 alterations: a prospective, open-label, single-arm phase 2 study (PATHER2). BMC Med 2022; 20:277. [PMID: 36031613 PMCID: PMC9422117 DOI: 10.1186/s12916-022-02470-6] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Accepted: 07/08/2022] [Indexed: 11/30/2022] Open
Abstract
BACKGROUND Although targeted agents have been gradually applied in the treatment of HER2-mutated non-small cell lung cancer (NSCLC) in recent years, patients' therapeutic demands are far from being met. PATHER2 was the first phase 2 trial to explore the efficacy and safety of the HER2-targeted tyrosine kinase inhibitor (TKI) pyrotinib plus the antiangiogenic agent apatinib in previously treated HER2-altered metastatic NSCLC patients. METHODS HER2-mutated or HER2-amplified metastatic NSCLC patients who had failed at least first-line chemotherapy or HER2-targeted TKIs received oral pyrotinib 400 mg plus apatinib 250 mg once daily until disease progression, intolerable toxicity, or death. The primary endpoint was the investigator-assessed objective response rate (ORR). RESULTS Between March 2019 and December 2020, 33 patients were enrolled; 13 (39.4%) presented brain metastases, and 16 (48.5%) had received at least two lines of prior chemotherapy or HER2-targeted TKIs. As of September 20, 2021, the median follow-up duration was 11.3 (range, 3.5-26.0) months. The investigator-assessed ORR was 51.5% (17/33; 95% CI, 33.5 to 69.2%), and the disease control rate was 93.9% (31/33; 95% CI, 79.8 to 99.3%). The median duration of response, progression-free survival, and overall survival were 6.0 (95% CI, 4.4 to 8.6) months, 6.9 (95% CI, 5.8 to 8.5) months, and 14.8 (95% CI, 10.4 to 23.8) months, respectively. The most frequent grade ≥ 3 treatment-related adverse events included diarrhea (3.0%) and hypertension (9.1%). No treatment-related deaths were reported. CONCLUSIONS Pyrotinib plus apatinib demonstrated promising antitumor activity and a manageable safety profile in HER2-mutated or HER2-amplified metastatic NSCLC patients. TRIAL REGISTRATION Chinese Clinical Trial Registry Identifier: ChiCTR1900021684 .
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Affiliation(s)
- Guangjian Yang
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No.17 Panjiayuan Street South, Chaoyang District, Beijing, 100021, China.,Department of Respiratory Medicine, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250117, Shandong, China
| | - Haiyan Xu
- Department of Comprehensive Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Yaning Yang
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No.17 Panjiayuan Street South, Chaoyang District, Beijing, 100021, China
| | - Shuyang Zhang
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No.17 Panjiayuan Street South, Chaoyang District, Beijing, 100021, China
| | - Fei Xu
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No.17 Panjiayuan Street South, Chaoyang District, Beijing, 100021, China
| | - Xuezhi Hao
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No.17 Panjiayuan Street South, Chaoyang District, Beijing, 100021, China
| | - Junling Li
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No.17 Panjiayuan Street South, Chaoyang District, Beijing, 100021, China
| | - Puyuan Xing
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No.17 Panjiayuan Street South, Chaoyang District, Beijing, 100021, China
| | - Xingsheng Hu
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No.17 Panjiayuan Street South, Chaoyang District, Beijing, 100021, China
| | - Yutao Liu
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No.17 Panjiayuan Street South, Chaoyang District, Beijing, 100021, China
| | - Lin Wang
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No.17 Panjiayuan Street South, Chaoyang District, Beijing, 100021, China
| | - Lin Lin
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No.17 Panjiayuan Street South, Chaoyang District, Beijing, 100021, China
| | - Zhijie Wang
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No.17 Panjiayuan Street South, Chaoyang District, Beijing, 100021, China
| | - Jianchun Duan
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No.17 Panjiayuan Street South, Chaoyang District, Beijing, 100021, China
| | - Jie Wang
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No.17 Panjiayuan Street South, Chaoyang District, Beijing, 100021, China.
| | - Yan Wang
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No.17 Panjiayuan Street South, Chaoyang District, Beijing, 100021, China.
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Metabolic Reprogramming in Cancer Cells: Emerging Molecular Mechanisms and Novel Therapeutic Approaches. Pharmaceutics 2022; 14:pharmaceutics14061303. [PMID: 35745875 PMCID: PMC9227908 DOI: 10.3390/pharmaceutics14061303] [Citation(s) in RCA: 57] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2022] [Revised: 06/01/2022] [Accepted: 06/13/2022] [Indexed: 12/03/2022] Open
Abstract
The constant changes in cancer cell bioenergetics are widely known as metabolic reprogramming. Reprogramming is a process mediated by multiple factors, including oncogenes, growth factors, hypoxia-induced factors, and the loss of suppressor gene function, which support malignant transformation and tumor development in addition to cell heterogeneity. Consequently, this hallmark promotes resistance to conventional anti-tumor therapies by adapting to the drastic changes in the nutrient microenvironment that these therapies entail. Therefore, it represents a revolutionary landscape during cancer progression that could be useful for developing new and improved therapeutic strategies targeting alterations in cancer cell metabolism, such as the deregulated mTOR and PI3K pathways. Understanding the complex interactions of the underlying mechanisms of metabolic reprogramming during cancer initiation and progression is an active study field. Recently, novel approaches are being used to effectively battle and eliminate malignant cells. These include biguanides, mTOR inhibitors, glutaminase inhibition, and ion channels as drug targets. This review aims to provide a general overview of metabolic reprogramming, summarise recent progress in this field, and emphasize its use as an effective therapeutic target against cancer.
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27
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Saheli M, Khoramipour K, Vosough M, Piryaei A, Rahmati M, Suzuki K. Athletes' Mesenchymal Stem Cells Could Be the Best Choice for Cell Therapy in Omicron-Infected Patients. Cells 2022; 11:1926. [PMID: 35741055 PMCID: PMC9221912 DOI: 10.3390/cells11121926] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2022] [Revised: 06/08/2022] [Accepted: 06/12/2022] [Indexed: 02/05/2023] Open
Abstract
New severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant, Omicron, contains 32 mutations that have caused a high incidence of breakthrough infections or re-infections. These mutations have reduced vaccine protection against Omicron and other new emerging variants. This highlights the need to find effective treatment, which is suggested to be stem cell-based therapy. Stem cells could support respiratory epithelial cells and they could restore alveolar bioenergetics. In addition, they can increase the secretion of immunomodulatory cytokines. However, after transplantation, cell survival and growth rate are low because of an inappropriate microenvironment, and stem cells face ischemia, inflammation, and oxidative stress in the transplantation niche which reduces the cells' survival and growth. Exercise-training can upregulate antioxidant, anti-inflammatory, and anti-apoptotic defense mechanisms and increase growth signaling, thereby improving transplanted cells' survival and growth. Hence, using athletes' stem cells may increase stem-cell therapy outcomes in Omicron-affected patients.
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Affiliation(s)
- Mona Saheli
- Department of Anatomical Sciences, and Pathology and Stem Cell Research Centre, Afzalipour Faculty of Medicine, Kerman University of Medical Sciences, Kerman 7616914115, Iran;
| | - Kayvan Khoramipour
- Neuroscience Research Center, Institute of Neuropharmacology, and Department of Physiology and Pharmacology, Afzalipour School of Medicine, Kerman University of Medical Sciences, Kerman 7616914115, Iran
- Student Research Committee, Kerman University of Medical Sciences, Kerman 7619813159, Iran
| | - Massoud Vosough
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran 1665659911, Iran;
- Experimental Cancer Medicine, Institution for Laboratory Medicine, Karolinska Institute, 17177 Stockholm, Sweden
| | - Abbas Piryaei
- Department of Biology and Anatomical Sciences, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran 1985717443, Iran;
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran 1434875451, Iran
| | - Masoud Rahmati
- Department of Physical Education and Sport Sciences, Faculty of Literature and Human Sciences, Lorestan University, Khoramabad 6815144316, Iran;
| | - Katsuhiko Suzuki
- Faculty of Sport Sciences, Waseda University, Tokorozawa 359-1192, Saitama, Japan
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MAPK/ERK-CBP-RFPL-3 Mediates Adipose-Derived Stem Cell-Induced Tumor Growth in Breast Cancer Cells by Activating Telomerase Reverse Transcriptase Expression. Stem Cells Int 2022; 2022:8540535. [PMID: 35711680 PMCID: PMC9197637 DOI: 10.1155/2022/8540535] [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: 11/18/2021] [Revised: 04/16/2022] [Accepted: 04/29/2022] [Indexed: 11/26/2022] Open
Abstract
Adipose-derived stem cells (ASCs) improve the self-renewal and survival of fat grafts in breast reconstruction after oncology surgery. However, ASCs have also been found to enhance breast cancer growth, and its role in tumor proliferation remains largely elusive. Here, we explored a novel mechanism that mediates hTERT reactivation during ASC-induced tumor growth in breast cancer cells. In this study, we found the proliferative ability of breast cancer cells markedly increased with ASC coculture. To explore the molecular mechanism, we treated cells with anibody/inhibitor and found that the activation of MEK-ERK pathway was triggered in breast cancer cells by SCF secreted from ASCs, leading to the nuclear recruitment of CBP. As a coactivator of hTERT, CBP subsequently coordinated with RFPL-3 upregulated hTERT transcription and telomerase activity. The inhibition of CBP and RFPL-3 abrogated the activation of hTERT transcription and the promotion of proliferation in breast cancer cells with cocultured ASCs in vitro and in vivo. Collectively, our study findings indicated that CBP coordination with RFPL-3 promotes ASC-induced breast cancer cell proliferation by anchoring to the hTERT promoter and upregulating telomerase activity, which is activated by the MAPK/ERK pathway.
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Blangé D, Stroes CI, Derks S, Bijlsma MF, van Laarhoven HW. Resistance Mechanisms to HER2-Targeted Therapy in Gastroesophageal Adenocarcinoma: A Systematic Review. Cancer Treat Rev 2022; 108:102418. [DOI: 10.1016/j.ctrv.2022.102418] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Revised: 05/20/2022] [Accepted: 05/22/2022] [Indexed: 12/16/2022]
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Effects of rifampicin on antineoplastic drug pyrotinib maleate pharmacokinetics in healthy subjects. Invest New Drugs 2022; 40:756-761. [DOI: 10.1007/s10637-022-01241-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Accepted: 03/24/2022] [Indexed: 12/11/2022]
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Bin YL, Hu HS, Tian F, Wen ZH, Yang MF, Wu BH, Wang LS, Yao J, Li DF. Metabolic Reprogramming in Gastric Cancer: Trojan Horse Effect. Front Oncol 2022; 11:745209. [PMID: 35096565 PMCID: PMC8790521 DOI: 10.3389/fonc.2021.745209] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Accepted: 11/12/2021] [Indexed: 12/24/2022] Open
Abstract
Worldwide, gastric cancer (GC) represents the fifth most common cancer for incidence and the third leading cause of death in developed countries. Despite the development of combination chemotherapies, the survival rates of GC patients remain unsatisfactory. The reprogramming of energy metabolism is a hallmark of cancer, especially increased dependence on aerobic glycolysis. In the present review, we summarized current evidence on how metabolic reprogramming in GC targets the tumor microenvironment, modulates metabolic networks and overcomes drug resistance. Preclinical and clinical studies on the combination of metabolic reprogramming targeted agents and conventional chemotherapeutics or molecularly targeted treatments [including vascular endothelial growth factor receptor (VEGFR) and HER2] and the value of biomarkers are examined. This deeper understanding of the molecular mechanisms underlying successful pharmacological combinations is crucial in finding the best-personalized treatment regimens for cancer patients.
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Affiliation(s)
- Yu-Ling Bin
- Department of Rheumatology and Immunology, ZhuZhou Central Hospital, Zhuzhou, China
| | - Hong-Sai Hu
- Department of Gastroenterology, ZhuZhou Central Hospital, Zhuzhou, China
| | - Feng Tian
- Department of Rheumatology and Immunology, ZhuZhou Central Hospital, Zhuzhou, China
| | - Zhen-Hua Wen
- Department of Rheumatology and Immunology, ZhuZhou Central Hospital, Zhuzhou, China
| | - Mei-Feng Yang
- Department of Hematology, Yantian District People's Hospital, Shenzhen, China
| | - Ben-Hua Wu
- Department of Gastroenterology, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, China
| | - Li-Sheng Wang
- Department of Gastroenterology, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, China
| | - Jun Yao
- Department of Gastroenterology, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, China
| | - De-Feng Li
- Department of Gastroenterology, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, China
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Zhang L, Chen Y, Lv Y, Jiao S, Zhao W. OUP accepted manuscript. Oncologist 2022; 27:245-250. [PMID: 35380719 DOI: 10.1093/oncolo/oyac027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2021] [Accepted: 12/28/2021] [Indexed: 11/12/2022] Open
Affiliation(s)
- Li Zhang
- Department of Oncology, PLA General Hospital, Beijing, People's Republic of China
| | - Yimeng Chen
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shanxi, People's Republic of China
| | - Yao Lv
- Department of Oncology, PLA General Hospital, Beijing, People's Republic of China
| | - Shunchang Jiao
- Department of Oncology, PLA General Hospital, Beijing, People's Republic of China
| | - Weihong Zhao
- Department of Oncology, PLA General Hospital, Beijing, People's Republic of China
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Abourehab MAS, Alqahtani AM, Youssif BGM, Gouda AM. Globally Approved EGFR Inhibitors: Insights into Their Syntheses, Target Kinases, Biological Activities, Receptor Interactions, and Metabolism. Molecules 2021; 26:6677. [PMID: 34771085 PMCID: PMC8587155 DOI: 10.3390/molecules26216677] [Citation(s) in RCA: 97] [Impact Index Per Article: 24.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Revised: 10/28/2021] [Accepted: 11/02/2021] [Indexed: 02/06/2023] Open
Abstract
Targeting the EGFR with small-molecule inhibitors is a confirmed valid strategy in cancer therapy. Since the FDA approval of the first EGFR-TKI, erlotinib, great efforts have been devoted to the discovery of new potent inhibitors. Until now, fourteen EGFR small-molecule inhibitors have been globally approved for the treatment of different types of cancers. Although these drugs showed high efficacy in cancer therapy, EGFR mutations have emerged as a big challenge for these drugs. In this review, we focus on the EGFR small-molecule inhibitors that have been approved for clinical uses in cancer therapy. These drugs are classified based on their chemical structures, target kinases, and pharmacological uses. The synthetic routes of these drugs are also discussed. The crystal structures of these drugs with their target kinases are also summarized and their bonding modes and interactions are visualized. Based on their binding interactions with the EGFR, these drugs are also classified into reversible and irreversible inhibitors. The cytotoxicity of these drugs against different types of cancer cell lines is also summarized. In addition, the proposed metabolic pathways and metabolites of the fourteen drugs are discussed, with a primary focus on the active and reactive metabolites. Taken together, this review highlights the syntheses, target kinases, crystal structures, binding interactions, cytotoxicity, and metabolism of the fourteen globally approved EGFR inhibitors. These data should greatly help in the design of new EGFR inhibitors.
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Affiliation(s)
- Mohammed A. S. Abourehab
- Department of Pharmaceutics, Faculty of Pharmacy, Umm Al-Qura University, Makkah 21955, Saudi Arabia;
| | - Alaa M. Alqahtani
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Umm Al-Qura University, Makkah 21955, Saudi Arabia
| | - Bahaa G. M. Youssif
- Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Assiut University, Assiut 71526, Egypt;
| | - Ahmed M. Gouda
- Department of Medicinal Chemistry, Faculty of pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt
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Ye G, Zhang J, Zhang C. Stimulator of interferon response cGAMP interactor overcomes ERBB2-mediated apatinib resistance in head and neck squamous cell carcinoma. Aging (Albany NY) 2021; 13:20793-20807. [PMID: 34459788 PMCID: PMC8436913 DOI: 10.18632/aging.203475] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Accepted: 07/09/2021] [Indexed: 02/07/2023]
Abstract
PURPOSE Apatinib resistance is the main obstacle to the effective treatment of advanced head and neck squamous cell carcinoma (HNSCC). This study aimed to evaluate the function of Erb-B2 receptor tyrosine kinase 2 (ERBB2) and stimulator of interferon response cGAMP interactor (STING) in apatinib resistance in HNSCC. METHOD The Cancer Genome Atlas database of HNSCC was used to analyze the relationship between vascular endothelial growth factor receptor 2 (VEGFR2) expression and prognosis. An apatinib resistant (AR) HNSCC cell line was constructed based on the CAL27 cell line. RNA sequencing was performed to explore the differentially expressed mRNAs. Quantitative real-time reverse transcription PCR (qRT-PCR) and western blotting were used to evaluate the expression and phosphorylation level VEGFR2, ERBB2, STING, and related proteins. Apatinib resistance was evaluated by colony formation and cell viability assays. A mouse subcutaneous tumor formation model was established to evaluate the efficiency of combination treatment and vascularization was evaluated by assessing CD31 immunofluorescence. RESULT The expression of VEGFR2 was high in tumor of patients with HNSCC. Western blotting and qRT-PCR revealed that in AR cells, ERBB2 expression was high, whereas the expression of STING was low. Targeted treatment of ERBB2 using lapatinib could attenuate apatinib resistance. Further research confirmed that overexpressing STING could decrease ERBB2 expression. CONCLUSION STING could sensitize AR cells to apatinib by decreasing ERBB2 expression. The combination of lapatinib or a STING agonist with apatinib ameliorated acquired apatinib resistance in a synergistic manner.
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Affiliation(s)
- Guo Ye
- Department of Head and Neck Cancer Center, Chongqing University Cancer Hospital, Chongqing 400030, China
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital, Chongqing 400030, China
| | - Junbin Zhang
- Department of Head and Neck Cancer Center, Chongqing University Cancer Hospital, Chongqing 400030, China
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital, Chongqing 400030, China
| | - Chengyao Zhang
- Department of Head and Neck Cancer Center, Chongqing University Cancer Hospital, Chongqing 400030, China
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital, Chongqing 400030, China
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Hu Y, Su F, Dong K, Wang X, Zhao X, Jiang Y, Li J, Ji J, Sun Y. Deep learning system for lymph node quantification and metastatic cancer identification from whole-slide pathology images. Gastric Cancer 2021; 24:868-877. [PMID: 33484355 DOI: 10.1007/s10120-021-01158-9] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2020] [Accepted: 01/07/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND Traditional diagnosis methods for lymph node metastases are labor-intensive and time-consuming. As a result, diagnostic systems based on deep learning (DL) algorithms have become a hot topic. However, current research lacks testing with sufficient data to verify performance. The aim of this study was to develop and test a deep learning system capable of identifying lymph node metastases. METHODS 921 whole-slide images of lymph nodes were divided into two cohorts: training and testing. For lymph node quantification, we combined Faster RCNN and DeepLab as a cascade DL algorithm to detect regions of interest. For metastatic cancer identification, we fused Xception and DenseNet-121 models and extracted features. Prospective testing to verify the performance of the diagnostic system was performed using 327 unlabeled images. We further validated the proposed system using Positive Predictive Value (PPV) and Negative Predictive Value (NPV) criteria. RESULTS We developed a DL-based system capable of automated quantification and identification of metastatic lymph nodes. The accuracy of lymph node quantification was shown to be 97.13%. The PPV of the combined Xception and DenseNet-121 model was 93.53%, and the NPV was 97.99%. Our experimental results show that the differentiation level of metastatic cancer affects the recognition performance. CONCLUSIONS The diagnostic system we established reached a high level of efficiency and accuracy of lymph node diagnosis. This system could potentially be implemented into clinical workflow to assist pathologists in making a preliminary screening for lymph node metastases in gastric cancer patients.
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Affiliation(s)
- Yajie Hu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Pathology, Peking University Cancer Hospital and Institute, 52 Fucheng Road, Haidian District, Beijing, 100142, China
| | - Feng Su
- Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, 100871, China
| | - Kun Dong
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Pathology, Peking University Cancer Hospital and Institute, 52 Fucheng Road, Haidian District, Beijing, 100142, China
| | - Xinyu Wang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Pathology, Peking University Cancer Hospital and Institute, 52 Fucheng Road, Haidian District, Beijing, 100142, China
| | - Xinya Zhao
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Pathology, Peking University Cancer Hospital and Institute, 52 Fucheng Road, Haidian District, Beijing, 100142, China
| | - Yumeng Jiang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Pathology, Peking University Cancer Hospital and Institute, 52 Fucheng Road, Haidian District, Beijing, 100142, China
| | - Jianming Li
- Institute for Artificial Intelligence, The State Key Laboratory of Intelligence Technology and Systems, Beijing National Research Center for Information Science and Technology, Department of Computer Science and Technology, Tsinghua University, Beijing, 100084, China
| | - Jiafu Ji
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Gastrointestinal Cancer Center, Peking University Cancer Hospital and Institute, Beijing, 100142, China
| | - Yu Sun
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Pathology, Peking University Cancer Hospital and Institute, 52 Fucheng Road, Haidian District, Beijing, 100142, China.
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Apatinib suppresses lung cancer stem-like cells by complex interplay between β-catenin signaling and mitochondrial ROS accumulation. Cell Death Discov 2021; 7:102. [PMID: 33980809 PMCID: PMC8115647 DOI: 10.1038/s41420-021-00480-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Revised: 03/21/2021] [Accepted: 04/13/2021] [Indexed: 02/07/2023] Open
Abstract
The abnormal activation of Wnt/β-catenin signaling plays a critical role in the development of lung cancer, which is also important in the generation and maintenance of lung cancer stem cell (CSC). CSCs have unique capabilities to resist anticancer therapy, seed recurrent tumors, and disseminate to and colonize distant tissues. Apatinib, a small-molecule VEGFR2-tyrosine kinase inhibitor, shows highly efficient antitumor activity in heavily treated, chemoresistant, and metastatic lung cancer. We speculated that inhibition of Wnt/β-catenin signaling and targeting lung CSCs could be one of the anti-tumor mechanisms of apatinib. In the present study we demonstrated that apatinib repressed lung CSC-like traits by hindering sphere formation ability, lung CSC-related marker expression and decreasing chemoresistance derived stemness. Mechanistically, apatinib exerted its anti-CSC effects by inhibiting β-catenin and its downstream targets. Moreover, apatinib induced the production of reactive oxyen species (ROS), which participated in the inhibitory effects of apatinib on lung CSCs. It was found that β-catenin regulated apatinib-induced production of ROS. Inhibition or promotion of ROS production with N-acetyl-L-cysteine or H2O2 not only upregulated or downregulated β-catenin expression, but also prevented or promoted DNA damage, rescued or impeded sphere formation, respectively. Collectively, our findings reveal that apatinib directly inhibits β-catenin signaling and promotes ROS generation to suppress lung CSC-like characteristics. A clearer understanding of the anti-cancer mechanisms of apatinib is required for its better application in combating advanced and refractory/recurrent lung cancer when combined with conventional chemotherapy.
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Hao P, Huang Y, Peng J, Yu J, Guo X, Bao F, Dian Z, An S, Xu TR. IRS4 promotes the progression of non-small cell lung cancer and confers resistance to EGFR-TKI through the activation of PI3K/Akt and Ras-MAPK pathways. Exp Cell Res 2021; 403:112615. [PMID: 33894221 DOI: 10.1016/j.yexcr.2021.112615] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2020] [Revised: 03/13/2021] [Accepted: 04/16/2021] [Indexed: 12/16/2022]
Abstract
IRS4 is a member of the insulin receptor substrate (IRS) protein family. It acts as a cytoplasmic adaptor protein, integrating and transmitting signals from receptor protein tyrosine kinases to the intracellular environment. IRS4 can induce mammary tumorigenesis and is usually overexpressed in non-small cell lung cancer (NSCLC). However, little is known about the role of IRS4 in the development and progression of lung cancer. In this study, we show that IRS4 knockout suppresses the proliferation, colony formation, migration, and invasion of A549 lung cancer cells, as well as tumor growth in a nude mouse xenograft model. In contrast, stable expression of IRS4 showed the opposite effects. As expected, IRS4 was found to activate the PI3K/Akt and Ras-MAPK pathways, and we also showed that IRS4 depletion significantly enhanced the sensitivity of EGFR tyrosine kinase inhibitor (EGFR-TKI)-resistant cells to gefitinib. Taken together, these results show that IRS4 promotes NSCLC progression and may represent a potential therapeutic target for EGFR-TKI-resistant NSCLC.
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MESH Headings
- Animals
- Antineoplastic Agents/therapeutic use
- Carcinoma, Non-Small-Cell Lung/drug therapy
- Carcinoma, Non-Small-Cell Lung/genetics
- Carcinoma, Non-Small-Cell Lung/metabolism
- Carcinoma, Non-Small-Cell Lung/pathology
- Cell Line, Tumor
- Cell Movement/drug effects
- Cell Proliferation/drug effects
- Drug Resistance, Neoplasm/genetics
- ErbB Receptors/genetics
- ErbB Receptors/metabolism
- Extracellular Signal-Regulated MAP Kinases/genetics
- Extracellular Signal-Regulated MAP Kinases/metabolism
- Gefitinib/therapeutic use
- Gene Expression Regulation, Neoplastic
- Humans
- Insulin Receptor Substrate Proteins/antagonists & inhibitors
- Insulin Receptor Substrate Proteins/genetics
- Insulin Receptor Substrate Proteins/metabolism
- Lung Neoplasms/drug therapy
- Lung Neoplasms/genetics
- Lung Neoplasms/metabolism
- Lung Neoplasms/pathology
- Male
- Mice
- Mice, Nude
- Phosphatidylinositol 3-Kinases/genetics
- Phosphatidylinositol 3-Kinases/metabolism
- Proto-Oncogene Proteins c-akt/genetics
- Proto-Oncogene Proteins c-akt/metabolism
- RNA, Small Interfering/genetics
- RNA, Small Interfering/metabolism
- Signal Transduction
- Tumor Burden/drug effects
- Xenograft Model Antitumor Assays
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Affiliation(s)
- Peiqi Hao
- Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, 650500, China
| | - Ying Huang
- Simcere Pharmaceutical Co., Ltd, Nanjing, 210018, China; The State Key Laboratory of Translational Medicine and Innovative Drug Development, Jiangsu Simcere Pharmaceutical Co., Ltd, Nanjing, 210018, China
| | - Jun Peng
- The First People's Hospital of Yunnan Province, Kunming, 650032, China
| | - Jiaojiao Yu
- Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, 650500, China
| | - Xiaoxi Guo
- Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, 650500, China
| | - Fan Bao
- Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, 650500, China; The First People's Hospital of Yunnan Province, Kunming, 650032, China
| | - Ziqin Dian
- The First People's Hospital of Yunnan Province, Kunming, 650032, China
| | - Su An
- Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, 650500, China.
| | - Tian-Rui Xu
- Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, 650500, China.
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Ding K, Chen X, Li Y, Li W, Ye Y, He T, Wang W, Zhang H. Gastric Cancer Harboring an ERBB3 Mutation Treated with a Pyrotinib-Irinotecan Combo: A Case Study. Onco Targets Ther 2021; 14:545-550. [PMID: 33500629 PMCID: PMC7823137 DOI: 10.2147/ott.s286024] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2020] [Accepted: 12/04/2020] [Indexed: 12/09/2022] Open
Abstract
Gastric cancer is common, especially in East Asian countries, and is associated with high recurrence and mortality rates. Currently, there is no standard third-line treatment for metastatic gastric cancer. In this report, we present the case of a 69-year-old man with advanced gastric cancer, whose tumor was negative for human epidermal growth factor receptor 2 (HER2) according to immunohistochemical analysis. Next-generation sequencing performed on paraffin sections of the postoperative tumor samples indicated the presence of the ERBB3 V104L mutation. The patient received irinotecan plus pyrotinib as a third-line therapy and achieved a progression-free survival of 7.6 months with a high quality of life. Therefore, the combined administration of irinotecan and pyrotinib may improve the clinical condition of patients with gastric cancer harboring an ERBB3 mutation. Moreover, ERBB3 could be a potential therapeutic target for gastric cancer.
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Affiliation(s)
- Kailin Ding
- The Second Clinical College, Guangzhou University of Chinese Medicine, Guangzhou, People's Republic of China
| | - Xian Chen
- Department of Oncology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, People's Republic of China
| | - Yong Li
- Department of Oncology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, People's Republic of China
| | - Wenzhu Li
- Department of Oncology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, People's Republic of China
| | - Yongsong Ye
- Department of Imaging, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, People's Republic of China
| | - Tingting He
- OrigiMed, Shanghai, People's Republic of China
| | | | - Haibo Zhang
- Department of Oncology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, People's Republic of China
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