|
1
|
Shah A, Decoste R, Vanderbeck K, Sharma A, Roy SF, Naert K, Osmond A. Molecular-Guided Therapy for Melanoma in Canada: Overview of Current Practices and Recommendations. J Cutan Med Surg 2024:12034754241303057. [PMID: 39661469 DOI: 10.1177/12034754241303057] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2024]
Abstract
The emergence of pathologist-driven molecular reflex testing for tumoural biomarkers is a significant advancement in cancer diagnostics, facilitating targeted cancer therapy for our patients. Based on our experience, the Canadian landscape of pathologist-driven reflex biomarker testing for melanoma lacks standardization and is plagued by a lack of awareness by pathologists and clinicians. This paper comprehensively examines the approaches to reflex biomarker testing for melanoma patients across Canada, highlighting the regional variations in the criteria for initiating molecular testing, the biomarkers tested, and the molecular techniques employed. We also discuss the clinical relevance of biomarkers, emphasizing their alignment with the National Comprehensive Cancer Network® (NCCN®) Clinical Practice Guidelines in Oncology (NCCN Guidelines®) as well as ancillary tests such as BRAF VE1 immunohistochemistry to detect BRAF V600E mutation and molecular techniques such as real-time polymerase chain reaction, matrix-assisted laser desorption ionization-time of flight mass spectrometry and next-generation sequencing. Our proposed standardized minimum criteria for reflex testing prioritize melanomas with Breslow thickness >4 mm or disseminated disease, who will most benefit from enhanced delivery of biomarkers and expedited access to targeted therapies while attempting to balance cost-effectiveness and utilization of public healthcare resources with patient outcomes.
Collapse
Affiliation(s)
- Ahmed Shah
- Department of Pathology and Laboratory Medicine, University of Calgary, Calgary, AB, Canada
- Alberta Precision Laboratories, Calgary, AB, Canada
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
| | - Ryan Decoste
- Department of Pathology, Nova Scotia Health (Central Zone) and Dalhousie University, Halifax, NS, Canada
| | - Kaitlin Vanderbeck
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
| | - Anurag Sharma
- Pathology and Laboratory Medicine, Western University, London, ON, Canada
| | - Simon F Roy
- Department of Dermatology, Yale University, New Haven, CT, USA
| | - Karen Naert
- Department of Pathology and Laboratory Medicine, University of Calgary, Calgary, AB, Canada
- Alberta Precision Laboratories, Calgary, AB, Canada
| | - Allison Osmond
- Department of Diagnostic and Molecular Pathology, Memorial University of Newfoundland, Health Sciences Centre, St. John's, NL, Canada
| |
Collapse
|
|
2
|
Chaudhary HA, Cannon TL, Winer A. Targeting Non-V600 Mutations in BRAF: A Single Institution Retrospective Analysis and Review of the Literature. Drugs R D 2024; 24:395-403. [PMID: 39177935 PMCID: PMC11455815 DOI: 10.1007/s40268-024-00475-5] [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: 06/23/2024] [Indexed: 08/24/2024] Open
Abstract
BACKGROUND AND OBJECTIVE While successful treatment paradigms for BRAF V600 mutations have been developed, 10% of BRAF mutations are not at V600 and lack a standard treatment regimen. This study summarizes the current body of knowledge on the treatment of non-V600 mutations and reports a single institution experience. METHODS We conducted a literature review to summarize relevant preclinical and clinical published data on the response of non-V600 mutations to targeted therapies. We performed a retrospective analysis of INOVA Schar Cancer patients registered in our Molecular Tumor Board database with non-V600 BRAF mutations who were recipients of targeted therapy and assessed their time to next treatment and best response. RESULTS Published preclinical and clinical data have demonstrated limiting results in the response of non-V600 mutated cancers to targeted therapies. Response rates were variable for the major classes of BRAF mutations including class II and class III mutations as well as, BRAF fusions. Data collected from our INOVA cohort offered promising results with one patient achieving partial remission and two patients achieving stable disease. CONCLUSIONS This article reflects the current understanding of targeted therapies in non-V600 mutations. Further large-scale studies separating BRAF mutations based on their mechanism of activation will expand our understanding.
Collapse
Affiliation(s)
- Hirra A Chaudhary
- INOVA, Schar Cancer Institute, Fairfax, VA, USA.
- UVA School of Medicine, INOVA Fairfax Medical Campus, Fairfax, VA, USA.
| | | | | |
Collapse
|
|
3
|
Chen YK, Kanouni T, Arnold LD, Cox JM, Gardiner E, Grandinetti K, Jiang P, Kaldor SW, Lee C, Li C, Martin ES, Miller N, Murphy EA, Timple N, Tyhonas JS, Vassar A, Wang TS, Williams R, Yuan D, Kania RS. The Discovery of Exarafenib (KIN-2787): Overcoming the Challenges of Pan-RAF Kinase Inhibition. J Med Chem 2024; 67:1747-1757. [PMID: 38230963 DOI: 10.1021/acs.jmedchem.3c01830] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2024]
Abstract
RAF, a core signaling component of the MAPK kinase cascade, is often mutated in various cancers, including melanoma, lung, and colorectal cancers. The approved inhibitors were focused on targeting the BRAFV600E mutation that results in constitutive activation of kinase signaling through the monomeric protein (Class I). However, these inhibitors also paradoxically activate kinase signaling of RAF dimers, resulting in increased MAPK signaling in normal tissues. Recently, significant attention has turned to targeting RAF alterations that activate dimeric signaling (class II and III BRAF and NRAS). However, the discovery of a potent and selective inhibitor with biopharmaceutical properties suitable to sustain robust target inhibition in the clinical setting has proven challenging. Herein, we report the discovery of exarafenib (15), a highly potent and selective inhibitor that intercepts the RAF protein in the dimer compatible αC-helix-IN conformation and demonstrates anti-tumor efficacy in preclinical models with BRAF class I, II, and III and NRAS alterations.
Collapse
Affiliation(s)
- Young K Chen
- Kinnate Biopharma, 12830 El Camino Real, Suite 150, San Diego, California 92130, United States
| | - Toufike Kanouni
- Kinnate Biopharma, 12830 El Camino Real, Suite 150, San Diego, California 92130, United States
| | - Lee D Arnold
- Kinnate Biopharma, 12830 El Camino Real, Suite 150, San Diego, California 92130, United States
| | - Jason M Cox
- Kinnate Biopharma, 12830 El Camino Real, Suite 150, San Diego, California 92130, United States
| | - Elisabeth Gardiner
- Kinnate Biopharma, 12830 El Camino Real, Suite 150, San Diego, California 92130, United States
| | - Kathryn Grandinetti
- Kinnate Biopharma, 12830 El Camino Real, Suite 150, San Diego, California 92130, United States
| | - Ping Jiang
- Kinnate Biopharma, 12830 El Camino Real, Suite 150, San Diego, California 92130, United States
| | - Stephen W Kaldor
- Kinnate Biopharma, 12830 El Camino Real, Suite 150, San Diego, California 92130, United States
| | - Catherine Lee
- Kinnate Biopharma, 12830 El Camino Real, Suite 150, San Diego, California 92130, United States
| | - Chun Li
- Kinnate Biopharma, 12830 El Camino Real, Suite 150, San Diego, California 92130, United States
| | - Eric S Martin
- Kinnate Biopharma, 12830 El Camino Real, Suite 150, San Diego, California 92130, United States
| | - Nichol Miller
- Kinnate Biopharma, 12830 El Camino Real, Suite 150, San Diego, California 92130, United States
| | - Eric A Murphy
- Kinnate Biopharma, 12830 El Camino Real, Suite 150, San Diego, California 92130, United States
| | - Noel Timple
- Kinnate Biopharma, 12830 El Camino Real, Suite 150, San Diego, California 92130, United States
| | - John S Tyhonas
- Kinnate Biopharma, 12830 El Camino Real, Suite 150, San Diego, California 92130, United States
| | - Angie Vassar
- Kinnate Biopharma, 12830 El Camino Real, Suite 150, San Diego, California 92130, United States
| | - Tim S Wang
- Kinnate Biopharma, 12830 El Camino Real, Suite 150, San Diego, California 92130, United States
| | - Richard Williams
- Kinnate Biopharma, 12830 El Camino Real, Suite 150, San Diego, California 92130, United States
| | - Ding Yuan
- Kinnate Biopharma, 12830 El Camino Real, Suite 150, San Diego, California 92130, United States
| | - Robert S Kania
- Kinnate Biopharma, 12830 El Camino Real, Suite 150, San Diego, California 92130, United States
| |
Collapse
|
|
4
|
Riaud M, Maxwell J, Soria-Bretones I, Dankner M, Li M, Rose AAN. The role of CRAF in cancer progression: from molecular mechanisms to precision therapies. Nat Rev Cancer 2024; 24:105-122. [PMID: 38195917 DOI: 10.1038/s41568-023-00650-x] [Citation(s) in RCA: 10] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/27/2023] [Indexed: 01/11/2024]
Abstract
The RAF family of kinases includes key activators of the pro-tumourigenic mitogen-activated protein kinase pathway. Hyperactivation of RAF proteins, particularly BRAF and CRAF, drives tumour progression and drug resistance in many types of cancer. Although BRAF is the most studied RAF protein, partially owing to its high mutation incidence in melanoma, the role of CRAF in tumourigenesis and drug resistance is becoming increasingly clinically relevant. Here, we summarize the main known regulatory mechanisms and gene alterations that contribute to CRAF activity, highlighting the different oncogenic roles of CRAF, and categorize RAF1 (CRAF) mutations according to the effect on kinase activity. Additionally, we emphasize the effect that CRAF alterations may have on drug resistance and how precision therapies could effectively target CRAF-dependent tumours. Here, we discuss preclinical and clinical findings that may lead to improved treatments for all types of oncogenic RAF1 alterations in cancer.
Collapse
Affiliation(s)
- Melody Riaud
- Gerald Bronfman Department of Oncology, McGill University, Montreal, Quebec, Canada
- Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, Canada
| | - Jennifer Maxwell
- Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, Canada
- Division of Experimental Medicine, Faculty of Medicine, McGill University, Montreal, Quebec, Canada
| | - Isabel Soria-Bretones
- Gerald Bronfman Department of Oncology, McGill University, Montreal, Quebec, Canada
- Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, Canada
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
| | - Matthew Dankner
- Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, Canada
- Faculty of Medicine, McGill University, Montreal, Quebec, Canada
- Rosalind & Morris Goodman Cancer Institute, McGill University, Montreal, Quebec, Canada
| | - Meredith Li
- Gerald Bronfman Department of Oncology, McGill University, Montreal, Quebec, Canada
| | - April A N Rose
- Gerald Bronfman Department of Oncology, McGill University, Montreal, Quebec, Canada.
- Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, Canada.
- Division of Experimental Medicine, Faculty of Medicine, McGill University, Montreal, Quebec, Canada.
| |
Collapse
|
|
5
|
Liu J, Hu X, Xin W, Wang X. Exosomal Non-coding RNAs: A New Approach to Melanoma Diagnosis and Therapeutic Strategy. Curr Med Chem 2024; 31:6084-6109. [PMID: 37877505 DOI: 10.2174/0109298673267553231017053329] [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: 06/15/2023] [Revised: 09/03/2023] [Accepted: 09/22/2023] [Indexed: 10/26/2023]
Abstract
Malignant melanoma (MM) is a highly aggressive cancer with a poor prognosis. Currently, although a variety of therapies are available for treating melanoma, MM is still a serious threat to the patient's life due to numerous factors, such as the recurrence of tumors, the emergence of drug resistance, and the lack of effective therapeutic agents. Exosomes are biologically active lipid-bilayer extracellular vesicles secreted by diverse cell types that mediate intercellular signal communication. Studies found that exosomes are involved in cancer by carrying multiple bioactive molecules, including non-- coding RNAs (ncRNAs). The ncRNAs have been reported to play an important role in regulating proliferation, angiogenesis, immune regulation, invasion, metastasis, and treatment resistance of tumors. However, the functional role of exosomal ncRNAs in MM remains unknown. Therefore, this review summarizes the current state of melanoma diagnosis, treatment, and the application of exosomal ncRNAs in MM patients, which may provide new insights into the mechanisms involved in melanoma progression and serve as biomarkers for diagnosis and therapeutic targets.
Collapse
Affiliation(s)
- Jie Liu
- Department of Dermatology, Skin Research Institute of Peking University Shenzhen Hospital, Peking University Shenzhen Hospital, Shenzhen 518036, Guangdong Province, China
| | - Xiaoping Hu
- Department of Dermatology, Skin Research Institute of Peking University Shenzhen Hospital, Peking University Shenzhen Hospital, Shenzhen 518036, Guangdong Province, China
| | - Wenqiang Xin
- Department of Neurology, University Medical Center Göttingen, Göttingen 37075, Germany
- Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, China, 300052
| | - Xianbin Wang
- Department of Emergency Medicine, The Second Affiliated Hospital of Baotou Medical College, Baotou 014030, China
| |
Collapse
|
|
6
|
Wang P, Laster K, Jia X, Dong Z, Liu K. Targeting CRAF kinase in anti-cancer therapy: progress and opportunities. Mol Cancer 2023; 22:208. [PMID: 38111008 PMCID: PMC10726672 DOI: 10.1186/s12943-023-01903-x] [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: 08/31/2023] [Accepted: 11/16/2023] [Indexed: 12/20/2023] Open
Abstract
The RAS/mitogen-activated protein kinase (MAPK) signaling cascade is commonly dysregulated in human malignancies by processes driven by RAS or RAF oncogenes. Among the members of the RAF kinase family, CRAF plays an important role in the RAS-MAPK signaling pathway, as well as in the progression of cancer. Recent research has provided evidence implicating the role of CRAF in the physiological regulation and the resistance to BRAF inhibitors through MAPK-dependent and MAPK-independent mechanisms. Nevertheless, the effectiveness of solely targeting CRAF kinase activity remains controversial. Moreover, the kinase-independent function of CRAF may be essential for lung cancers with KRAS mutations. It is imperative to develop strategies to enhance efficacy and minimize toxicity in tumors driven by RAS or RAF oncogenes. The review investigates CRAF alterations observed in cancers and unravels the distinct roles of CRAF in cancers propelled by diverse oncogenes. This review also seeks to summarize CRAF-interacting proteins and delineate CRAF's regulation across various cancer hallmarks. Additionally, we discuss recent advances in pan-RAF inhibitors and their combination with other therapeutic approaches to improve treatment outcomes and minimize adverse effects in patients with RAF/RAS-mutant tumors. By providing a comprehensive understanding of the multifaceted role of CRAF in cancers and highlighting the latest developments in RAF inhibitor therapies, we endeavor to identify synergistic targets and elucidate resistance pathways, setting the stage for more robust and safer combination strategies for cancer treatment.
Collapse
Affiliation(s)
- Penglei Wang
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450000, China
- Tianjian Laboratory for Advanced Biomedical Sciences, Zhengzhou, 450052, Henan, China
- China-US (Henan) Hormel Cancer Institute, Zhengzhou, 450000, China
| | - Kyle Laster
- China-US (Henan) Hormel Cancer Institute, Zhengzhou, 450000, China
| | - Xuechao Jia
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450000, China
- Tianjian Laboratory for Advanced Biomedical Sciences, Zhengzhou, 450052, Henan, China
- China-US (Henan) Hormel Cancer Institute, Zhengzhou, 450000, China
| | - Zigang Dong
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450000, China.
- Tianjian Laboratory for Advanced Biomedical Sciences, Zhengzhou, 450052, Henan, China.
- China-US (Henan) Hormel Cancer Institute, Zhengzhou, 450000, China.
- Department of Pathophysiology, School of Basic Medical Sciences, China-US (Henan) Hormel Cancer Institute, AMS, College of Medicine, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, 450001, Henan, China.
| | - Kangdong Liu
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450000, China.
- Tianjian Laboratory for Advanced Biomedical Sciences, Zhengzhou, 450052, Henan, China.
- China-US (Henan) Hormel Cancer Institute, Zhengzhou, 450000, China.
- Department of Pathophysiology, School of Basic Medical Sciences, China-US (Henan) Hormel Cancer Institute, AMS, College of Medicine, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, 450001, Henan, China.
- Basic Medicine Sciences Research Center, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, 450052, Henan, China.
- State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou University, Zhengzhou, 450000, Henan, China.
- Provincial Cooperative Innovation Center for Cancer Chemoprevention, Zhengzhou University, Zhengzhou, 450000, Henan, China.
| |
Collapse
|
|
7
|
Chehrazi-Raffle A, Tukachinsky H, Toye E, Sivakumar S, Schrock AB, Bergom HE, Ebrahimi H, Pal S, Dorff T, Agarwal N, Mahal BA, Oxnard GR, Hwang J, Antonarakis ES. Unique Spectrum of Activating BRAF Alterations in Prostate Cancer. Clin Cancer Res 2023; 29:3948-3957. [PMID: 37477913 PMCID: PMC10543965 DOI: 10.1158/1078-0432.ccr-23-1393] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2023] [Revised: 06/17/2023] [Accepted: 07/20/2023] [Indexed: 07/22/2023]
Abstract
PURPOSE Alterations in BRAF have been reported in 3% to 5% of prostate cancer, although further characterization is lacking. Here, we describe the nature of BRAF alterations in prostate cancer using a large cohort from commercially available tissue and liquid biopsies subjected to comprehensive genomic profiling (CGP). EXPERIMENTAL DESIGN Tissue and liquid biopsies from patients with prostate cancer were profiled using FoundationOne CDx and FoundationOne Liquid CDx CGP assays, respectively. Tissue biopsies from non-prostate cancer types were used for comparison (n = 275,151). Genetic ancestry was predicted using a single-nucleotide polymorphism (SNP) based approach. RESULTS Among 15,864 tissue biopsies, BRAF-activating alterations were detected in 520 cases (3.3%). The majority (463 samples, 2.9%) harbored class II alterations, including BRAF rearrangements (243 samples, 1.5%), K601E (101 samples, 0.6%), and G469A (58 samples, 0.4%). BRAF-altered prostate cancers were enriched for CDK12 mutations (OR, 1.87; 9.2% vs. 5.2%; P = 0.018), but depleted in TMPRSS2 fusions (OR, 0.25; 11% vs. 32%; P < 0.0001), PTEN alterations (OR, 0.47; 17% vs. 31%; P < 0.0001), and APC alterations (OR, 0.48; 4.4% vs. 8.9%; P = 0.018) relative to BRAF wild-type (WT) disease. Compared with patients of European ancestry, BRAF alterations were more common in tumors from patients of African ancestry (5.1% vs. 2.9%, P < 0.0001) and Asian ancestry (6.0% vs. 2.9%, P < 0.001). CONCLUSIONS Activating BRAF alterations were detected in approximately 3% of prostate cancers, and most were class II mutations and rearrangements; BRAF V600 mutations were exceedingly rare. These findings suggest that BRAF activation in prostate cancer is unique from other cancers and supports further clinical investigation of therapeutics targeting the mitogen-activated protein kinase (MAPK) pathway.
Collapse
Affiliation(s)
| | | | - Eamon Toye
- Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota
| | | | | | - Hannah E. Bergom
- Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota
| | - Hedyeh Ebrahimi
- City of Hope Comprehensive Cancer Center, Duarte, California
| | - Sumanta Pal
- City of Hope Comprehensive Cancer Center, Duarte, California
| | - Tanya Dorff
- City of Hope Comprehensive Cancer Center, Duarte, California
| | - Neeraj Agarwal
- Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah
| | - Brandon A. Mahal
- Sylvester Comprehensive Cancer Center, University of Miami, Miami, Florida
| | | | - Justin Hwang
- Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota
| | | |
Collapse
|
|
8
|
Lauinger M, Christen D, Klar RF, Roubaty C, Heilig CE, Stumpe M, Knox JJ, Radulovich N, Tamblyn L, Xie IY, Horak P, Forschner A, Bitzer M, Wittel UA, Boerries M, Ball CR, Heining C, Glimm H, Fröhlich M, Hübschmann D, Gallinger S, Fritsch R, Fröhling S, O’Kane GM, Dengjel J, Brummer T. BRAF Δβ3-αC in-frame deletion mutants differ in their dimerization propensity, HSP90 dependence, and druggability. SCIENCE ADVANCES 2023; 9:eade7486. [PMID: 37656784 PMCID: PMC11804575 DOI: 10.1126/sciadv.ade7486] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/08/2022] [Accepted: 08/02/2023] [Indexed: 09/03/2023]
Abstract
In-frame BRAF exon 12 deletions are increasingly identified in various tumor types. The resultant BRAFΔβ3-αC oncoproteins usually lack five amino acids in the β3-αC helix linker and sometimes contain de novo insertions. The dimerization status of BRAFΔβ3-αC oncoproteins, their precise pathomechanism, and their direct druggability by RAF inhibitors (RAFi) has been under debate. Here, we functionally characterize BRAFΔLNVTAP>F and two novel mutants, BRAFdelinsFS and BRAFΔLNVT>F, and compare them with other BRAFΔβ3-αC oncoproteins. We show that BRAFΔβ3-αC oncoproteins not only form stable homodimers and large multiprotein complexes but also require dimerization. Nevertheless, details matter as aromatic amino acids at the deletion junction of some BRAFΔβ3-αC oncoproteins, e.g., BRAFΔLNVTAP>F, increase their stability and dimerization propensity while conferring resistance to monomer-favoring RAFi such as dabrafenib or HSP 90/CDC37 inhibition. In contrast, dimer-favoring inhibitors such as naporafenib inhibit all BRAFΔβ3-αC mutants in cell lines and patient-derived organoids, suggesting that tumors driven by such oncoproteins are vulnerable to these compounds.
Collapse
Affiliation(s)
- Manuel Lauinger
- Institute of Molecular Medicine, ZBMZ, Faculty of Medicine, University of Freiburg, 79104 Freiburg, Germany
- Faculty of Biology, University of Freiburg, Freiburg, Germany
| | - Daniel Christen
- Institute of Molecular Medicine, ZBMZ, Faculty of Medicine, University of Freiburg, 79104 Freiburg, Germany
- Faculty of Biology, University of Freiburg, Freiburg, Germany
- German Cancer Consortium (DKTK), partner site Freiburg and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
| | - Rhena F. U. Klar
- Institute of Molecular Medicine, ZBMZ, Faculty of Medicine, University of Freiburg, 79104 Freiburg, Germany
- Faculty of Biology, University of Freiburg, Freiburg, Germany
- German Cancer Consortium (DKTK), partner site Freiburg and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
- Freeze-O Organoid Bank, University Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
- Department of Internal Medicine I (Hematology, Oncology, and Stem Cell Transplantation), University Hospital of Freiburg, Freiburg, Germany
- Institute of Medical Bioinformatics and Systems Medicine (IBSM), Freiburg University Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Carole Roubaty
- Department of Biology, University of Fribourg, 1700 Fribourg, Switzerland
| | - Christoph E. Heilig
- Division of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Heidelberg and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
- German Cancer Consortium (DKTK), Heidelberg, Germany
| | - Michael Stumpe
- Department of Biology, University of Fribourg, 1700 Fribourg, Switzerland
| | - Jennifer J. Knox
- PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
| | - Nikolina Radulovich
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
| | - Laura Tamblyn
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
| | - Irene Y. Xie
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
| | - Peter Horak
- Division of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Heidelberg and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
- German Cancer Consortium (DKTK), Heidelberg, Germany
| | - Andrea Forschner
- Department of Dermatology, University Hospital of Tübingen, Tübingen, Germany
- German Cancer Consortium (DKTK), DKFZ partner site Tübingen, Eberhard Karls University, Tübingen, Germany
| | - Michael Bitzer
- German Cancer Consortium (DKTK), DKFZ partner site Tübingen, Eberhard Karls University, Tübingen, Germany
- Center for Personalized Medicine Tübingen, Eberhard Karls University, Tübingen, Germany
- Department of Internal Medicine I, Eberhard-Karls University, Tübingen, Germany
| | - Uwe A. Wittel
- Department of General and Visceral Surgery, University of Freiburg Medical Center, Faculty of Medicine, 79106 Freiburg, Germany
| | - Melanie Boerries
- German Cancer Consortium (DKTK), partner site Freiburg and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
- Institute of Medical Bioinformatics and Systems Medicine (IBSM), Freiburg University Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
- Comprehensive Cancer Center Freiburg (CCCF), Medical Center, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
| | - Claudia R. Ball
- Department for Translational Medical Oncology, National Center for Tumor Diseases (NCT/UCC), Dresden, Germany
- German Cancer Research Center (DKFZ), Heidelberg, Germany
- Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
- Helmholtz-Zentrum Dresden–Rossendorf (HZDR), Dresden, Germany
- Translational Medical Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
- German Cancer Consortium (DKTK), Dresden, Germany
- Technische Universität Dresden, Faculty of Biology, Technische Universität Dresden, Dresden, Germany
| | - Christoph Heining
- Department for Translational Medical Oncology, National Center for Tumor Diseases (NCT/UCC), Dresden, Germany
- German Cancer Research Center (DKFZ), Heidelberg, Germany
- Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
- Helmholtz-Zentrum Dresden–Rossendorf (HZDR), Dresden, Germany
- Translational Medical Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
- German Cancer Consortium (DKTK), Dresden, Germany
| | - Hanno Glimm
- Department for Translational Medical Oncology, National Center for Tumor Diseases (NCT/UCC), Dresden, Germany
- German Cancer Research Center (DKFZ), Heidelberg, Germany
- Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
- Helmholtz-Zentrum Dresden–Rossendorf (HZDR), Dresden, Germany
- Translational Medical Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
- German Cancer Consortium (DKTK), Dresden, Germany
- Translational Functional Cancer Genomics, National Center for Tumor Diseases (NCT) and German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Martina Fröhlich
- Computational Oncology Group, Molecular Precision Oncology Program, National Center for Tumor Diseases (NCT) Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Daniel Hübschmann
- German Cancer Consortium (DKTK), Heidelberg, Germany
- Computational Oncology Group, Molecular Precision Oncology Program, National Center for Tumor Diseases (NCT) Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany
- Pattern Recognition and Digital Medicine Group, Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM), Heidelberg, Germany
| | - Steven Gallinger
- PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
| | - Ralph Fritsch
- Department of Internal Medicine I (Hematology, Oncology, and Stem Cell Transplantation), University Hospital of Freiburg, Freiburg, Germany
- Department of Medical Oncology and Haematology, University Hospital of Zurich, Zurich, Switzerland
| | - Stefan Fröhling
- Division of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Heidelberg and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
- German Cancer Consortium (DKTK), Heidelberg, Germany
| | - Grainne M. O’Kane
- PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
| | - Jörn Dengjel
- Department of Biology, University of Fribourg, 1700 Fribourg, Switzerland
| | - Tilman Brummer
- Institute of Molecular Medicine, ZBMZ, Faculty of Medicine, University of Freiburg, 79104 Freiburg, Germany
- German Cancer Consortium (DKTK), partner site Freiburg and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
- Freeze-O Organoid Bank, University Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
- Comprehensive Cancer Center Freiburg (CCCF), Medical Center, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
- Center for Biological Signalling Studies BIOSS, University of Freiburg, 79104 Freiburg, Germany
| |
Collapse
|
|
9
|
Wagner SA. Clinical associations and genetic interactions of oncogenic BRAF alleles. PeerJ 2022; 10:e14126. [PMID: 36275468 PMCID: PMC9586110 DOI: 10.7717/peerj.14126] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Accepted: 09/06/2022] [Indexed: 01/21/2023] Open
Abstract
BRAF is a serine/threonine-specific protein kinase that regulates the MAPK/ERK signaling pathway, and mutations in the BRAF gene are considered oncogenic drivers in diverse types of cancer. Based on the signaling mechanism, oncogenic BRAF mutations can be assigned to three different classes: class 1 mutations constitutively activate the kinase domain and lead to RAS-independent signaling, class 2 mutations induce artificial dimerization of BRAF and RAS-independent signaling and class 3 mutations display reduced or abolished kinase function and require upstream signals. Despite the importance of BRAF mutations in cancer, the clinical associations, genetic interactions and therapeutic implications of non-V600 BRAF mutations have not been explored comprehensively yet. In this study, the author analyzed publically available data from the AACR Project GENIE to further understand clinical associations and genetic interactions of oncogenic BRAF mutations. The analyses identified 93 recurrent BRAF mutations, out of which 50 could be assigned to a functional class based on literature review. The author could show that the frequency of BRAF mutations varies across cancer types and subtypes, and that the BRAF mutation classes are unequally distributed across cancer types and subtypes. Using permutation testing-based co-occurrence analyses, the author defined the genetic interactions of BRAF mutations in multiple cancer types and revealed unexplored genetic interactions that might define clinically relevant subgroups. With non-small cell lung cancer as example, the author further showed that the genetic interactions are BRAF mutation class-specific. The presented analyses explore the properties of oncogenic BRAF mutations and will help to further delineate the complex role of BRAF in cancer.
Collapse
Affiliation(s)
- Sebastian A. Wagner
- Department of Medicine, Hematology/Oncology, Goethe University, Frankfurt, Germany,Frankfurt Cancer Institute (FCI), Frankfurt, Germany,German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany
| |
Collapse
|
|
10
|
Gong YY, Shao H, Li Y, Brafford P, Stine ZE, Sun J, Felsher DW, Orange JS, Albelda SM, Dang CV. Na +/H +-exchanger 1 enhances antitumor activity of engineered NK-92 natural killer cells. CANCER RESEARCH COMMUNICATIONS 2022; 2:842-856. [PMID: 36380966 PMCID: PMC9648415 DOI: 10.1158/2767-9764.crc-22-0270] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Revised: 07/27/2022] [Accepted: 07/28/2022] [Indexed: 06/16/2023]
Abstract
Adoptive cell transfer (ACT) immunotherapy has remarkable efficacy against some hematological malignancies. However, its efficacy in solid tumors is limited by the adverse tumor microenvironment (TME) conditions, most notably that acidity inhibits T and natural killer (NK) cell mTOR complex 1 (mTORC1) activity and impairs cytotoxicity. In several reported studies, systemic buffering of tumor acidity enhanced the efficacy of immune checkpoint inhibitors. Paradoxically, we found in a c-Myc-driven hepatocellular carcinoma model that systemic buffering increased tumor mTORC1 activity, negating inhibition of tumor growth by anti-PD1 treatment. Therefore, in this proof-of-concept study, we tested the metabolic engineering of immune effector cells to mitigate the inhibitory effect of tumor acidity while avoiding side effects associated with systemic buffering. We first overexpressed an activated RHEB in the human NK cell line NK-92, thereby rescuing acid-blunted mTORC1 activity and enhancing cytolytic activity. Then, to directly mitigate the effect of acidity, we ectopically expressed acid extruder proteins. Whereas ectopic expression of carbonic anhydrase IX (CA9) moderately increased mTORC1 activity, it did not enhance effector function. In contrast, overexpressing a constitutively active Na+/H+-exchanger 1 (NHE1; SLC9A1) in NK-92 did not elevate mTORC1 but enhanced degranulation, target engagement, in vitro cytotoxicity, and in vivo antitumor activity. Our findings suggest the feasibility of overcoming the inhibitory effect of the TME by metabolically engineering immune effector cells, which can enhance ACT for better efficacy against solid tumors.
Collapse
Affiliation(s)
- Yao-Yu Gong
- Cell and Molecular Biology Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | | | - Yu Li
- Department of Pediatrics, Columbia University Medical Center, New York, New York
| | | | | | - Jing Sun
- Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Dean W. Felsher
- Division of Oncology, Department of Medicine, Stanford University School of Medicine, Stanford, California
| | - Jordan S. Orange
- Department of Pediatrics, Columbia University Medical Center, New York, New York
| | - Steven M. Albelda
- Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Chi V. Dang
- The Wistar Institute, Philadelphia, Pennsylvania
- Ludwig Institute for Cancer Research, New York, New York
| |
Collapse
|
|
11
|
Wolfe Z, Friedland JC, Ginn S, Blackham A, Demberger L, Horton M, McIntosh A, Sheikh H, Box J, Knoerzer D, Federowicz B, Stuhlmiller TJ, Shapiro M, Nair S. Case report: response to the ERK1/2 inhibitor ulixertinib in BRAF D594G cutaneous melanoma. Melanoma Res 2022; 32:295-298. [PMID: 35551160 PMCID: PMC9245552 DOI: 10.1097/cmr.0000000000000830] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Accepted: 04/07/2022] [Indexed: 11/26/2022]
Abstract
Melanoma is characterized by oncogenic mutations in pathways regulating cell growth, proliferation, and metabolism. Greater than 80% of primary melanoma cases harbor aberrant activation of the mitogen-activated protein kinase kinase/extracellular-signal-regulated kinase (MEK/ERK) pathway, with oncogenic mutations in BRAF, most notably BRAF V600E, being the most common. Significant progress has been made in BRAF-mutant melanoma using BRAF and MEK inhibitors; however, non-V600 BRAF mutations remain a challenge with limited treatment options. We report the case of an individual diagnosed with stage III BRAF D594G-mutant melanoma who experienced an extraordinary response to the ERK1/2 inhibitor ulixertinib as fourth-line therapy. Ulixertinib was obtained via an intermediate expanded access protocol with unique flexibility to permit both single-agent and combination treatments, dose adjustments, breaks in treatment to undergo surgery, and long-term preventive treatment following surgical resection offering this patient the potential for curative treatment.
Collapse
Affiliation(s)
- Zachary Wolfe
- Department of Hematology/Oncology, Lehigh Valley Topper Cancer Institute, Allentown, Pennsylvania
| | | | - Sarah Ginn
- xCures, Inc., Oakland, California, Departments of
| | | | - Lauren Demberger
- Department of Hematology/Oncology, Lehigh Valley Topper Cancer Institute, Allentown, Pennsylvania
| | - Morgan Horton
- Department of Hematology/Oncology, Lehigh Valley Topper Cancer Institute, Allentown, Pennsylvania
| | | | - Hina Sheikh
- Pathology, Lehigh Valley Topper Cancer Institute, Allentown, Pennsylvania
| | - Jessica Box
- BioMed Valley Discoveries, Kansas City, Missouri, USA
| | | | | | | | - Mark Shapiro
- xCures, Inc., Oakland, California, Departments of
| | - Suresh Nair
- Department of Hematology/Oncology, Lehigh Valley Topper Cancer Institute, Allentown, Pennsylvania
| |
Collapse
|
|
12
|
Bjorklund DM, Morgan RML, Oberoi J, Day KLIM, Galliou PA, Prodromou C. Recognition of BRAF by CDC37 and Re-Evaluation of the Activation Mechanism for the Class 2 BRAF-L597R Mutant. Biomolecules 2022; 12:biom12070905. [PMID: 35883461 PMCID: PMC9313131 DOI: 10.3390/biom12070905] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Revised: 06/21/2022] [Accepted: 06/23/2022] [Indexed: 11/16/2022] Open
Abstract
The kinome specific co-chaperone, CDC37 (cell division cycle 37), is responsible for delivering BRAF (B-Rapidly Accelerated Fibrosarcoma) to the Hsp90 (heat shock protein 90) complex, where it is then translocated to the RAS (protooncogene product p21) complex at the plasma membrane for RAS mediated dimerization and subsequent activation. We identify a bipartite interaction between CDC37 and BRAF and delimitate the essential structural elements of CDC37 involved in BRAF recognition. We find an extended and conserved CDC37 motif, 20HPNID---SL--W31, responsible for recognizing the C-lobe of BRAF kinase domain, while the c-terminal domain of CDC37 is responsible for the second of the bipartite interaction with BRAF. We show that dimerization of BRAF, independent of nucleotide binding, can act as a potent signal that prevents CDC37 recognition and discuss the implications of mutations in BRAF and the consequences on signaling in a clinical setting, particularly for class 2 BRAF mutations.
Collapse
Affiliation(s)
- Dennis M. Bjorklund
- Biochemistry and Biomedicine, School of Life Sciences, University of Sussex, Falmer, Brighton BN1 9QG, UK;
| | - R. Marc L. Morgan
- Department of Life Sciences, Faculty of Natural Sciences, South Kensington Campus, Imperial College London, London SW7 2AZ, UK;
| | - Jasmeen Oberoi
- Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Falmer, Brighton BN1 9RQ, UK;
| | | | - Panagiota A. Galliou
- Laboratory of Biological Chemistry, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece;
| | - Chrisostomos Prodromou
- Biochemistry and Biomedicine, School of Life Sciences, University of Sussex, Falmer, Brighton BN1 9QG, UK;
- Correspondence:
| |
Collapse
|
|
13
|
Horak P, Griffith M, Danos AM, Pitel BA, Madhavan S, Liu X, Chow C, Williams H, Carmody L, Barrow-Laing L, Rieke D, Kreutzfeldt S, Stenzinger A, Tamborero D, Benary M, Rajagopal PS, Ida CM, Lesmana H, Satgunaseelan L, Merker JD, Tolstorukov MY, Campregher PV, Warner JL, Rao S, Natesan M, Shen H, Venstrom J, Roy S, Tao K, Kanagal-Shamanna R, Xu X, Ritter DI, Pagel K, Krysiak K, Dubuc A, Akkari YM, Li XS, Lee J, King I, Raca G, Wagner AH, Li MM, Plon SE, Kulkarni S, Griffith OL, Chakravarty D, Sonkin D. Standards for the classification of pathogenicity of somatic variants in cancer (oncogenicity): Joint recommendations of Clinical Genome Resource (ClinGen), Cancer Genomics Consortium (CGC), and Variant Interpretation for Cancer Consortium (VICC). Genet Med 2022; 24:986-998. [PMID: 35101336 PMCID: PMC9081216 DOI: 10.1016/j.gim.2022.01.001] [Citation(s) in RCA: 98] [Impact Index Per Article: 32.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Revised: 12/22/2021] [Accepted: 01/03/2022] [Indexed: 01/21/2023] Open
Abstract
PURPOSE Several professional societies have published guidelines for the clinical interpretation of somatic variants, which specifically address diagnostic, prognostic, and therapeutic implications. Although these guidelines for the clinical interpretation of variants include data types that may be used to determine the oncogenicity of a variant (eg, population frequency, functional, and in silico data or somatic frequency), they do not provide a direct, systematic, and comprehensive set of standards and rules to classify the oncogenicity of a somatic variant. This insufficient guidance leads to inconsistent classification of rare somatic variants in cancer, generates variability in their clinical interpretation, and, importantly, affects patient care. Therefore, it is essential to address this unmet need. METHODS Clinical Genome Resource (ClinGen) Somatic Cancer Clinical Domain Working Group and ClinGen Germline/Somatic Variant Subcommittee, the Cancer Genomics Consortium, and the Variant Interpretation for Cancer Consortium used a consensus approach to develop a standard operating procedure (SOP) for the classification of oncogenicity of somatic variants. RESULTS This comprehensive SOP has been developed to improve consistency in somatic variant classification and has been validated on 94 somatic variants in 10 common cancer-related genes. CONCLUSION The comprehensive SOP is now available for classification of oncogenicity of somatic variants.
Collapse
Affiliation(s)
- Peter Horak
- National Center for Tumor Diseases (NCT), German Cancer Research Center (DKFZ), Heidelberg, Germany.
| | - Malachi Griffith
- Washington University School of Medicine in St. Louis, St. Louis, MO
| | - Arpad M Danos
- Washington University School of Medicine in St. Louis, St. Louis, MO
| | | | | | - Xuelu Liu
- Dana-Farber Cancer Institute, Boston, MA
| | - Cynthia Chow
- BC Cancer Agency, Vancouver, British Columbia, Canada
| | | | - Leigh Carmody
- The Jackson Laboratory for Genomic Medicine, Farmington, CT
| | | | - Damian Rieke
- Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Simon Kreutzfeldt
- National Center for Tumor Diseases (NCT), German Cancer Research Center (DKFZ), Heidelberg, Germany
| | | | | | | | - Padma Sheila Rajagopal
- Cancer Data Science Laboratory, Center for Cancer Research, National Cancer Institute, Bethesda, MD
| | | | - Harry Lesmana
- Genomic Medicine Institute, Cleveland Clinic Lerner Research Institute, Cleveland, OH
| | | | - Jason D Merker
- UNC School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC
| | | | | | | | - Shruti Rao
- Georgetown University Medical Center, Washington, DC
| | - Maya Natesan
- Washington University School of Medicine in St. Louis, St. Louis, MO
| | - Haolin Shen
- Washington University School of Medicine in St. Louis, St. Louis, MO
| | | | - Somak Roy
- Cincinnati Children's Hospital Medical Center, Cincinnati, OH
| | - Kayoko Tao
- National Cancer Center Hospital, Tokyo, Japan
| | | | | | | | - Kym Pagel
- Johns Hopkins University, Baltimore, MD
| | - Kilannin Krysiak
- Washington University School of Medicine in St. Louis, St. Louis, MO
| | - Adrian Dubuc
- Brigham and Women's Hospital, Harvard Medical School, Boston, MA
| | | | | | - Jennifer Lee
- Frederick National Laboratory for Cancer Research, National Cancer Institute, Rockville, MD
| | - Ian King
- University Health Network, Toronto, Ontario, Canada
| | - Gordana Raca
- University of Southern California, Los Angeles, CA
| | - Alex H Wagner
- Nationwide Children's Hospital, Columbus, OH; The Ohio State University College of Medicine, Columbus, OH
| | - Marylin M Li
- Children's Hospital of Philadelphia, Philadelphia, PA
| | | | | | - Obi L Griffith
- Washington University School of Medicine in St. Louis, St. Louis, MO
| | | | | |
Collapse
|
|
14
|
Dai X, Zhang X, Yin Q, Hu J, Guo J, Gao Y, Snell AH, Inuzuka H, Wan L, Wei W. Acetylation-dependent regulation of BRAF oncogenic function. Cell Rep 2022; 38:110250. [PMID: 35045286 PMCID: PMC8813213 DOI: 10.1016/j.celrep.2021.110250] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2019] [Revised: 11/02/2021] [Accepted: 12/21/2021] [Indexed: 12/21/2022] Open
Abstract
Aberrant BRAF activation, including the BRAFV600E mutation, is frequently observed in human cancers. However, it remains largely elusive whether other types of post-translational modification(s) in addition to phosphorylation and ubiquitination-dependent regulation also modulate BRAF kinase activity. Here, we report that the acetyltransferase p300 activates the BRAF kinase by promoting BRAF K601 acetylation, a process that is antagonized by the deacetylase SIRT1. Notably, K601 acetylation facilitates BRAF dimerization with RAF proteins and KSR1. Furthermore, K601 acetylation promotes melanoma cell proliferation and contributes to BRAFV600E inhibitor resistance in BRAFV600E harboring melanoma cells. As such, melanoma patient-derived K601E oncogenic mutation mimics K601 acetylation to augment BRAF kinase activity. Our findings, therefore, uncover a layer of BRAF regulation and suggest p300 hyperactivation or SIRT1 deficiency as potential biomarkers to determine ERK activation in melanomas. In tumor cells, hyperactivation of the BRAF protein kinase propels uncontrolled cell proliferation. BRAF hyperactivation is also achieved through several post-translational mechanisms. Dai et al. present an acetylation-dependent regulation of BRAF kinase function in melanoma cells, which serves to enhance BRAF oncogenic function and contributes to BRAF inhibitor resistance.
Collapse
Affiliation(s)
- Xiangpeng Dai
- Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Laboratory of Organ Regeneration & Transplantation of the Ministry of Education, The First Hospital of Jilin University, Changchun 130061, PR China; National-local Joint Engineering Laboratory of Animal Models for Human Diseases, Changchun, Jilin 130061, PR China.
| | - Xiaoling Zhang
- Laboratory of Organ Regeneration & Transplantation of the Ministry of Education, The First Hospital of Jilin University, Changchun 130061, PR China; National-local Joint Engineering Laboratory of Animal Models for Human Diseases, Changchun, Jilin 130061, PR China
| | - Qing Yin
- Department of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, 12902 USF Magnolia Drive, Tampa, FL 33612, USA
| | - Jia Hu
- Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Liberalization Avenue, No. 1095, Wuhan 430030, PR China
| | - Jianping Guo
- Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510275, PR China
| | - Yang Gao
- Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, PR China
| | - Aidan H Snell
- Department of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, 12902 USF Magnolia Drive, Tampa, FL 33612, USA
| | - Hiroyuki Inuzuka
- Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
| | - Lixin Wan
- Department of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, 12902 USF Magnolia Drive, Tampa, FL 33612, USA.
| | - Wenyi Wei
- Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
| |
Collapse
|
|
15
|
Huang C, Radi RH, Arbiser JL. Mitochondrial Metabolism in Melanoma. Cells 2021; 10:cells10113197. [PMID: 34831420 PMCID: PMC8618235 DOI: 10.3390/cells10113197] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Revised: 11/11/2021] [Accepted: 11/13/2021] [Indexed: 11/16/2022] Open
Abstract
Melanoma and its associated alterations in cellular pathways have been growing areas of interest in research, especially as specific biological pathways are being elucidated. Some of these alterations include changes in the mitochondrial metabolism in melanoma. Many mitochondrial metabolic changes lead to differences in the survivability of cancer cells and confer resistance to targeted therapies. While extensive work has gone into characterizing mechanisms of resistance, the role of mitochondrial adaptation as a mode of resistance is not completely understood. In this review, we wish to explore mitochondrial metabolism in melanoma and how it impacts modes of resistance. There are several genes that play a major role in melanoma mitochondrial metabolism which require a full understanding to optimally target melanoma. These include BRAF, CRAF, SOX2, MCL1, TRAP1, RHOA, SRF, SIRT3, PTEN, and AKT1. We will be discussing the role of these genes in melanoma in greater detail. An enhanced understanding of mitochondrial metabolism and these modes of resistance may result in novel combinatorial and sequential therapies that may lead to greater therapeutic benefit.
Collapse
Affiliation(s)
- Christina Huang
- Department of Dermatology, School of Medicine, Emory University, Atlanta, GA 30322, USA; (C.H.); (R.H.R.)
| | - Rakan H. Radi
- Department of Dermatology, School of Medicine, Emory University, Atlanta, GA 30322, USA; (C.H.); (R.H.R.)
| | - Jack L. Arbiser
- Department of Dermatology, School of Medicine, Emory University, Atlanta, GA 30322, USA; (C.H.); (R.H.R.)
- Atlanta Veterans Administration Medical Center, Decatur, GA 30033, USA
- Winship Cancer Institute, Emory University, Atlanta, GA 30322, USA
- Correspondence: ; Tel.: +1-(404)-727-5063; Fax: +1-(404)-727-0923
| |
Collapse
|
|
16
|
Ullah R, Yin Q, Snell AH, Wan L. RAF-MEK-ERK pathway in cancer evolution and treatment. Semin Cancer Biol 2021; 85:123-154. [PMID: 33992782 DOI: 10.1016/j.semcancer.2021.05.010] [Citation(s) in RCA: 235] [Impact Index Per Article: 58.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Revised: 05/03/2021] [Accepted: 05/06/2021] [Indexed: 12/13/2022]
Abstract
The RAF-MEK-ERK signaling cascade is a well-characterized MAPK pathway involved in cell proliferation and survival. The three-layered MAPK signaling cascade is initiated upon RTK and RAS activation. Three RAF isoforms ARAF, BRAF and CRAF, and their downstream MEK1/2 and ERK1/2 kinases constitute a coherently orchestrated signaling module that directs a range of physiological functions. Genetic alterations in this pathway are among the most prevalent in human cancers, which consist of numerous hot-spot mutations such as BRAFV600E. Oncogenic mutations in this pathway often override otherwise tightly regulated checkpoints to open the door for uncontrolled cell growth and neoplasia. The crosstalk between the RAF-MEK-ERK axis and other signaling pathways further extends the proliferative potential of this pathway in human cancers. In this review, we summarize the molecular architecture and physiological functions of the RAF-MEK-ERK pathway with emphasis on its dysregulations in human cancers, as well as the efforts made to target the RAF-MEK-ERK module using small molecule inhibitors.
Collapse
Affiliation(s)
- Rahim Ullah
- Department of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, 33612, USA
| | - Qing Yin
- Department of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, 33612, USA
| | - Aidan H Snell
- Department of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, 33612, USA
| | - Lixin Wan
- Department of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, 33612, USA; Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, 33612, USA.
| |
Collapse
|
|
17
|
Zhao Y, Yu H, Ida CM, Halling KC, Kipp BR, Geiersbach K, Rumilla KM, Gupta S, Lin MT, Zheng G. Assessment of RAS Dependency for BRAF Alterations Using Cancer Genomic Databases. JAMA Netw Open 2021; 4:e2035479. [PMID: 33507258 PMCID: PMC7844594 DOI: 10.1001/jamanetworkopen.2020.35479] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Accepted: 12/06/2020] [Indexed: 11/28/2022] Open
Abstract
IMPORTANCE Understanding RAS dependency and mechanisms of RAS activation in non-V600 BRAF variant cancers has important clinical implications. This is the first study to date to systematically assess RAS dependency of BRAF alterations with real-world cancer genomic databases. OBJECTIVE To evaluate RAS dependency of individual BRAF alterations through alteration coexistence analysis using cancer genomic databases. DESIGN AND SETTING A cross-sectional data analysis of 119 538 nonredundant cancer samples using cancer genomics databases including GENIE (Genomics Evidence Neoplasia Information Exchange) and databases in cBioPortal including TCGA (The Cancer Genome Atlas) (accessed March 24, 2020), in addition to 2745 cancer samples from Mayo Clinic Genomics Laboratory (January 1, 2015, to July 1, 2020). Frequencies and odds ratios of coexisting alterations of RAS (KRAS, NRAS and HRAS) and RAS regulatory genes (NF1, PTPN11 and CBL) were calculated for individual BRAF alterations, and compared according to the current BRAF alteration classification; cancer type specificity of coexisting alterations of RAS or RAS regulatory genes was also evaluated. MAIN OUTCOMES AND MEASURES Primary outcome measurement is enrichment of RAS (KRAS, NRAS and HRAS) alterations in BRAF variant cancers. Secondary outcome measurement is enrichment of RAS regulatory gene (NF1, PTPN11, and CBL) in BRAF variant cancers. RESULTS A total of 2745 cancer samples from 2708 patients (female/male ratio: 1.0) tested by Mayo Clinic Genomics Laboratory and 119 538 patients (female/male ratio: 1.1) from GENIE and cBioPortal database were included in the study. In 119 538 nonredundant cancer samples, class 1 BRAF alterations and BRAF fusions were found to be mutually exclusive to alterations of RAS or RAS regulatory genes (odds ratio range 0.03-0.13 and 0.03-0.73 respectively), confirming their RAS independency. Both class 2 and class 3 BRAF alterations show variable and overlapping levels of enriched RAS alterations (odds ratio range: 0.03-5.9 and 0.63-2.52 respectively), suggesting heterogeneity in RAS dependency and a need to revisit BRAF alteration classification. For RAS-dependent BRAF alterations, the coexisting alterations also involve RAS regulatory genes by enrichment analysis (for example, S467L shows an odds ratio of 8.26 for NF1, 9.87 for PTPN11, and 15.23 for CBL) and occur in a variety of cancer types with some coalterations showing cancer type specificity (for example, HRAS variations account for 46.7% of all coexisting RAS alterations in BRAF variant bladder cancers, but 0% in non-small cell lung cancers). Variant-level assessment shows that BRAF alterations involving the same codon may differ in RAS dependency. In addition, RAS dependency of previously unclassified BRAF alterations could be assessed. CONCLUSIONS AND RELEVANCE Current BRAF alteration classification based on in vitro assays does not accurately predict RAS dependency in vivo for non-V600 BRAF alterations. RAS-dependent BRAF variant cancers with different mechanisms of RAS activation suggest the need for different treatment strategies.
Collapse
Affiliation(s)
- Yiqing Zhao
- Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota
| | - Hanzhong Yu
- Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota
| | - Cris M. Ida
- Department of Pathology and Laboratory Medicine, Mayo Clinic, Rochester, Minnesota
| | - Kevin C. Halling
- Department of Pathology and Laboratory Medicine, Mayo Clinic, Rochester, Minnesota
| | - Benjamin R. Kipp
- Department of Pathology and Laboratory Medicine, Mayo Clinic, Rochester, Minnesota
| | - Katherine Geiersbach
- Department of Pathology and Laboratory Medicine, Mayo Clinic, Rochester, Minnesota
| | | | - Sounak Gupta
- Department of Pathology and Laboratory Medicine, Mayo Clinic, Rochester, Minnesota
| | - Ming-Tseh Lin
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Gang Zheng
- Department of Pathology and Laboratory Medicine, Mayo Clinic, Rochester, Minnesota
| |
Collapse
|
|
18
|
Janku F, Sakamuri D, Kato S, Huang HJ, Call SG, Naing A, Holley VR, Patel SP, Amaria RN, Falchook GS, Piha-Paul SA, Zinner RG, Tsimberidou AM, Hong DS, Meric-Bernstam F. Dose-escalation study of vemurafenib with sorafenib or crizotinib in patients with BRAF-mutated advanced cancers. Cancer 2020; 127:391-402. [PMID: 33119140 DOI: 10.1002/cncr.33242] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2020] [Revised: 08/09/2020] [Accepted: 08/28/2020] [Indexed: 01/07/2023]
Abstract
BACKGROUND BRAF inhibitors are effective in melanoma and other cancers with BRAF mutations; however, patients ultimately develop therapeutic resistance through the activation of alternative signaling pathways such as RAF/RAS or MET. The authors hypothesized that combining the BRAF inhibitor vemurafenib with either the multikinase inhibitor sorafenib or the MET inhibitor crizotinib could overcome therapeutic resistance. METHODS Patients with advanced cancers and BRAF mutations were enrolled in a dose-escalation study (3 + 3 design) to determine the maximum tolerated dose (MTD) and the dose-limiting toxicities (DLTs) of vemurafenib with sorafenib (VS) or vemurafenib with crizotinib (VC). RESULTS In total, 38 patients (VS, n = 24; VC, n = 14) were enrolled, and melanoma was the most represented tumor type (VS, 38%; VC, 64%). In the VS arm, vemurafenib 720 mg twice daily and sorafenib 400 mg am/200 mg pm were identified as the MTDs, DLTs included grade 3 rash (n = 2) and grade 3 hypertension, and partial responses were reported in 5 patients (21%), including 2 with ovarian cancer who had received previous treatment with BRAF, MEK, or ERK inhibitors. In the VC arm, vemurafenib 720 mg twice daily and crizotinib 250 mg daily were identified as the MTDs, DLTs included grade 3 rash (n = 2), and partial responses were reported in 4 patients (29%; melanoma, n = 3; lung adenocarcinoma, n = 1) who had received previous treatment with BRAF, MEK, and/or ERK inhibitors. Optional longitudinal collection of plasma to assess dynamic changes in circulating tumor DNA demonstrated the elimination of BRAF-mutant DNA from plasma during therapy (P = .005). CONCLUSIONS Vemurafenib combined with sorafenib or crizotinib was well tolerated with encouraging activity, including among patients who previously received treatment with BRAF, MEK, or ERK inhibitors.
Collapse
Affiliation(s)
- Filip Janku
- Department of Investigational Cancer Therapeutics (Phase 1 Clinical Trials Program), Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Divya Sakamuri
- Department of Investigational Cancer Therapeutics (Phase 1 Clinical Trials Program), Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Shumei Kato
- Department of Investigational Cancer Therapeutics (Phase 1 Clinical Trials Program), Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Helen J Huang
- Department of Investigational Cancer Therapeutics (Phase 1 Clinical Trials Program), Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - S Greg Call
- Department of Investigational Cancer Therapeutics (Phase 1 Clinical Trials Program), Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Aung Naing
- Department of Investigational Cancer Therapeutics (Phase 1 Clinical Trials Program), Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Veronica R Holley
- Department of Investigational Cancer Therapeutics (Phase 1 Clinical Trials Program), Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Sapna P Patel
- Department of Melanoma Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Rodabe N Amaria
- Department of Melanoma Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Gerald S Falchook
- Department of Investigational Cancer Therapeutics (Phase 1 Clinical Trials Program), Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.,Sarah Cannon Research Institute at HealthONE, Presbyterian/St Luke's Medical Center, Denver, Colorado
| | - Sarina A Piha-Paul
- Department of Investigational Cancer Therapeutics (Phase 1 Clinical Trials Program), Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Ralph G Zinner
- Department of Investigational Cancer Therapeutics (Phase 1 Clinical Trials Program), Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.,University of Kentucky Markey Cancer Center, Lexington, Kentucky
| | - Apostolia M Tsimberidou
- Department of Investigational Cancer Therapeutics (Phase 1 Clinical Trials Program), Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - David S Hong
- Department of Investigational Cancer Therapeutics (Phase 1 Clinical Trials Program), Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Funda Meric-Bernstam
- Department of Investigational Cancer Therapeutics (Phase 1 Clinical Trials Program), Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| |
Collapse
|
|
19
|
Targeting strategies for superparamagnetic iron oxide nanoparticles in cancer therapy. Acta Biomater 2020; 102:13-34. [PMID: 31759124 DOI: 10.1016/j.actbio.2019.11.027] [Citation(s) in RCA: 137] [Impact Index Per Article: 27.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2019] [Revised: 11/01/2019] [Accepted: 11/12/2019] [Indexed: 12/12/2022]
Abstract
Among various nanoparticles, superparamagnetic iron oxide nanoparticles (SPIONs) have been increasingly studied for their excellent superparamagnetism, magnetic heating properties, and enhanced magnetic resonance imaging (MRI). The conjugation of SPIONs with drugs to obtain delivery nanosystems has several advantages including magnetic targeted functionalization, in vivo imaging, magnetic thermotherapy, and combined delivery of anticancer agents. To further increase the targeting efficiency of drugs through a delivery nanosystem based on SPIONs, additional targeting moieties including transferrin, antibodies, aptamers, hyaluronic acid, folate, and targeting peptides are coated onto the surface of SPIONs. Therefore, this review summarizes the latest progresses in the conjugation of targeting molecules and drug delivery nanosystems based on SPIONs, especially focusing on their performances to develop efficient targeted drug delivery systems for tumor therapy. STATEMENT OF SIGNIFICANCE: Some magnetic nanoparticle-based nanocarriers loaded with drugs were evaluated in patients and did not produce convincing results, leading to termination of clinical development in phase II/III. An alternative strategy for drug delivery systems based on SPIONs is the conjugation of these systems with targeting segments such as transferrin, antibodies, aptamers, hyaluronic acid, folate, and targeting peptides. These targeting moieties can be recognized by specific integrin/receptors that are overexpressed specifically on the tumor cell surface, resulting in minimizing dosage and reducing off-target effects. This review focuses on magnetic nanoparticle-based nonviral drug delivery systems with targeting moieties to deliver anticancer drugs, with an aim to provide suggestions on the development of SPIONs through discussion.
Collapse
|
|
20
|
Han T, Zhang Y, Yang X, Han L, Li H, Chen T, Zheng Z. miR-552 Regulates Liver Tumor-Initiating Cell Expansion and Sorafenib Resistance. MOLECULAR THERAPY-NUCLEIC ACIDS 2020; 19:1073-1085. [PMID: 32044726 PMCID: PMC7015836 DOI: 10.1016/j.omtn.2019.12.043] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/06/2019] [Revised: 11/24/2019] [Accepted: 12/09/2019] [Indexed: 01/27/2023]
Abstract
MicroRNAs (miRNAs) are involved in tumorigenesis, progression, recurrence, and drug resistance of hepatocellular carcinoma (HCC). However, few miRNAs have been identified and entered clinical practice. Herein, we report that microRNA (miR)-552 is upregulated in HCC tissues and has an important function in liver tumor-initiating cells (T-ICs). Functional studies revealed that a forced expression of miR-552 promotes liver T-IC self-renewal and tumorigenesis. Conversely, miR-552 knockdown inhibits liver T-IC self-renewal and tumorigenesis. Mechanistically, miR-552 downregulates phosphatase and tensin homolog (PTEN) via its mRNA 3' UTR and activates protein kinase B (AKT) phosphorylation. Our clinical investigations elucidated the prognostic value of miR-552 in HCC patients. Furthermore, miR-552 expression determines the responses of hepatoma cells to sorafenib treatment. The analysis of patient cohorts and patient-derived xenografts (PDXs) further demonstrated that miR-552 may predict sorafenib benefits in HCC patients. In conclusion, our findings revealed the crucial role of the miR-552 in liver T-IC expansion and sorafenib response, rendering miR-552 an optimal target for the prevention and intervention in HCC.
Collapse
Affiliation(s)
- Tao Han
- Department of Oncology, General Hospital of Northern Theater Command, Shenyang, 110016 Liaoning Province, China; Department of Oncology, Second Affiliated Hospital of Dalian Medical University, Dalian, 116023, Liaoning Province, China
| | - Yue Zhang
- Department of Oncology, General Hospital of Northern Theater Command, Shenyang, 110016 Liaoning Province, China; Graduate School, Jinzhou Medical University, Jinzhou, 121000 Liaoning Province, China
| | - Xiaodan Yang
- Department of Oncology, General Hospital of Northern Theater Command, Shenyang, 110016 Liaoning Province, China
| | - Lei Han
- Department of Hepatobiliary Surgery, General Hospital of Northern Theater Command, Shenyang, 110016 Liaoning Province, China
| | - Hengyu Li
- Department of Breast and Thyroid Surgery, First Affiliated Hospital of Second Military Medical University, 200433 Shanghai, China.
| | - Tingsong Chen
- Department of Cancer Intervention, Shanghai Seventh People's Hospital, 200001 Shanghai, China.
| | - Zhendong Zheng
- Department of Oncology, General Hospital of Northern Theater Command, Shenyang, 110016 Liaoning Province, China.
| |
Collapse
|
|
21
|
Degirmenci U, Wang M, Hu J. Targeting Aberrant RAS/RAF/MEK/ERK Signaling for Cancer Therapy. Cells 2020; 9:E198. [PMID: 31941155 PMCID: PMC7017232 DOI: 10.3390/cells9010198] [Citation(s) in RCA: 366] [Impact Index Per Article: 73.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2019] [Revised: 12/29/2019] [Accepted: 01/10/2020] [Indexed: 12/13/2022] Open
Abstract
The RAS/RAF/MEK/ERK (MAPK) signaling cascade is essential for cell inter- and intra-cellular communication, which regulates fundamental cell functions such as growth, survival, and differentiation. The MAPK pathway also integrates signals from complex intracellular networks in performing cellular functions. Despite the initial discovery of the core elements of the MAPK pathways nearly four decades ago, additional findings continue to make a thorough understanding of the molecular mechanisms involved in the regulation of this pathway challenging. Considerable effort has been focused on the regulation of RAF, especially after the discovery of drug resistance and paradoxical activation upon inhibitor binding to the kinase. RAF activity is regulated by phosphorylation and conformation-dependent regulation, including auto-inhibition and dimerization. In this review, we summarize the recent major findings in the study of the RAS/RAF/MEK/ERK signaling cascade, particularly with respect to the impact on clinical cancer therapy.
Collapse
Affiliation(s)
- Ufuk Degirmenci
- Division of Cellular and Molecular Research, National Cancer Centre Singapore, 11 Hospital Crescent, Singapore 169610, Singapore
| | - Mei Wang
- Cancer and Stem Cell Biology Program, Duke-NUS Medical School, 8 College Road, Singapore 169857, Singapore
| | - Jiancheng Hu
- Division of Cellular and Molecular Research, National Cancer Centre Singapore, 11 Hospital Crescent, Singapore 169610, Singapore
- Cancer and Stem Cell Biology Program, Duke-NUS Medical School, 8 College Road, Singapore 169857, Singapore
| |
Collapse
|
|
22
|
Geyer JT, Yigit N, Miyaguchi A, Cheng S, Casano J, Mathew S, Desai P, Gergis U, Tam W. Histiocytic Sarcoma Following B-Lymphoblastic Leukemia/Lymphoma. Am J Clin Pathol 2019; 152:486-494. [PMID: 31172191 DOI: 10.1093/ajcp/aqz056] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
OBJECTIVES Rare cases of clonally related histiocytic sarcoma (HS) following B-lymphoblastic leukemia/lymphoma (B-ALL/LBL) have been reported to date. METHODS We present a patient with HS, which appeared as a breast mass 12 months after the initial diagnosis of B-ALL. RESULTS Both HS and the B-ALL shared IGH-MYC and IGK gene rearrangements. Next-generation sequencing and whole-exome sequencing (WES) studies detected 35 common mutations, as well as mutations unique to B-ALL (16) and HS (15), including BRAF D594G. The patient achieved complete remission of B-ALL, but HS failed to respond to many cycles of intensive chemotherapy regimens. A partial response was achieved with sorafenib, a BRAF-targeted therapy. CONCLUSIONS To our knowledge, this is the first study to demonstrate by WES that clonally related B-ALL and HS arise through divergent evolution from a common precursor. We present our findings together with a discussion of the previously reported cases of HS in patients with B-ALL.
Collapse
Affiliation(s)
- Julia T Geyer
- Departments of Pathology and Laboratory Medicine/NewYork-Presbyterian Hospital, New York, NY
| | - Nuri Yigit
- Departments of Pathology and Laboratory Medicine/NewYork-Presbyterian Hospital, New York, NY
| | - Ayako Miyaguchi
- Departments of Pathology and Laboratory Medicine/NewYork-Presbyterian Hospital, New York, NY
| | - Shuhua Cheng
- Departments of Pathology and Laboratory Medicine/NewYork-Presbyterian Hospital, New York, NY
| | - Joseph Casano
- Departments of Pathology and Laboratory Medicine/NewYork-Presbyterian Hospital, New York, NY
| | - Susan Mathew
- Departments of Pathology and Laboratory Medicine/NewYork-Presbyterian Hospital, New York, NY
| | - Pinkal Desai
- Departments of Medicine, Weill Cornell Medicine/NewYork-Presbyterian Hospital, New York, NY
| | - Usama Gergis
- Departments of Medicine, Weill Cornell Medicine/NewYork-Presbyterian Hospital, New York, NY
| | - Wayne Tam
- Departments of Pathology and Laboratory Medicine/NewYork-Presbyterian Hospital, New York, NY
| |
Collapse
|
|
23
|
Atypical BRAF and NRAS Mutations in Mucosal Melanoma. Cancers (Basel) 2019; 11:cancers11081133. [PMID: 31398831 PMCID: PMC6721527 DOI: 10.3390/cancers11081133] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2019] [Revised: 08/06/2019] [Accepted: 08/07/2019] [Indexed: 02/06/2023] Open
Abstract
Primary mucosal melanomas represent a minority of melanomas, but have a significantly worse prognosis than cutaneous melanomas. A better characterization of the molecular pathogenesis of this melanoma subtype could help us understand the risk factors associated with the development of mucosal melanomas and highlight therapeutic targets. Because the Mitogen-Activated Protein Kinase (MAPK) pathway plays such a significant role in melanoma development, we explore v-raf murine sarcoma viral oncogene homolog B (BRAF) and neuroblastoma RAS viral oncogene homolog (NRAS) mutations in mucosal melanoma and compare them to the mutation profiles in cutaneous melanoma and other tumors with BRAF and NRAS mutations. We show that in addition to being less frequent, BRAF and NRAS mutations are different in mucosal melanoma compared to cutaneous melanomas. Strikingly, the BRAF and NRAS mutation profiles in mucosal melanoma are closer to those found in cancers such as lung cancer, suggesting that mutations in mucosal melanoma could be linked to some genotoxic agents that remain to be identified. We also show that the atypical BRAF and NRAS mutations found in mucosal melanomas have particular effects on protein activities, which could be essential for the transformation of mucosal melanocytes.
Collapse
|
|
24
|
El Zaoui I, Bucher M, Rimoldi D, Nicolas M, Kaya G, Pescini Gobert R, Bedoni N, Schalenbourg A, Sakina E, Zografos L, Leyvraz S, Riggi N, Rivolta C, Moulin AP. Conjunctival Melanoma Targeted Therapy: MAPK and PI3K/mTOR Pathways Inhibition. ACTA ACUST UNITED AC 2019; 60:2764-2772. [DOI: 10.1167/iovs.18-26508] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Affiliation(s)
- Ikram El Zaoui
- Department of Computational Biology, Unit of Medical Genetics, Lausanne University, Lausanne, Switzerland
| | - Maya Bucher
- Dermatology Unit, CHUV, Lausanne University, Lausanne, Switzerland
| | - Donata Rimoldi
- Ludwig Institute for Cancer Research, Epalinges, Switzerland
| | - Michael Nicolas
- Jules-Gonin Eye Hospital, Lausanne University, FAA, Lausanne, Switzerland
| | - Gurkan Kaya
- Dermatology and Venerology Division, Dermatopathology Laboratory, Geneva University Hospital, Geneva, Switzerland
| | | | - Nicola Bedoni
- Department of Computational Biology, Unit of Medical Genetics, Lausanne University, Lausanne, Switzerland
| | - Ann Schalenbourg
- Jules-Gonin Eye Hospital, Lausanne University, FAA, Lausanne, Switzerland
| | - Ezziat Sakina
- Jules-Gonin Eye Hospital, Lausanne University, FAA, Lausanne, Switzerland
| | - Leonidas Zografos
- Jules-Gonin Eye Hospital, Lausanne University, FAA, Lausanne, Switzerland
| | - Serge Leyvraz
- Charité Cancer Comprehensive Center, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Nicolo Riggi
- Experimental Pathology, Lausanne University Pathology Institute, Lausanne, Switzerland
| | - Carlo Rivolta
- Department of Computational Biology, Unit of Medical Genetics, Lausanne University, Lausanne, Switzerland
- Department of Genetics and Genome Biology, University of Leicester, Leicester, United Kingdom
| | | |
Collapse
|
|
25
|
Using molecular dynamics simulation to explore the binding of the three potent anticancer drugs sorafenib, streptozotocin, and sunitinib to functionalized carbon nanotubes. J Mol Model 2019; 25:159. [DOI: 10.1007/s00894-019-4024-5] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2018] [Accepted: 04/02/2019] [Indexed: 01/07/2023]
|
|
26
|
Liu JY. Inhibition of Soluble Epoxide Hydrolase for Renal Health. Front Pharmacol 2019; 9:1551. [PMID: 30687105 PMCID: PMC6335332 DOI: 10.3389/fphar.2018.01551] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2018] [Accepted: 12/19/2018] [Indexed: 12/31/2022] Open
Abstract
A soluble epoxide hydrolase (sEH) mediates the metabolism of epoxy fatty acids to form the corresponding vicinal diols, which are usually inactive or less active than the epoxide substrates. The sEH enzyme presents in many organs, including but not limited to the liver, heart, spleen, lung, and kidney. Here we summarized the changes in the expression and activity of sEH in multiple renal diseases, such as acute kidney injury (AKI), diabetic nephrology (DN), chronic kidney diseases (CKD), hypertension-mediated renal damage, and other renal dysfunctions. We also discussed the pharmacologic effects and the underlying mechanisms of sEH inhibition by using an inhibitor of sEH and/or the generic deletion of sEH on multiple renal diseases. We believe that sEH is a potential therapeutic target for renal dysfunction although the target disease needs further investigation.
Collapse
Affiliation(s)
- Jun-Yan Liu
- Center for Nephrology and Metabolomics, Tongji University School of Medicine, Shanghai, China
- Division of Nephrology, Shanghai Tenth Peoples Hospital, Tongji University School of Medicine, Shanghai, China
| |
Collapse
|
|
27
|
Ip CKM, Ng PKS, Jeong KJ, Shao SH, Ju Z, Leonard PG, Hua X, Vellano CP, Woessner R, Sahni N, Scott KL, Mills GB. Neomorphic PDGFRA extracellular domain driver mutations are resistant to PDGFRA targeted therapies. Nat Commun 2018; 9:4583. [PMID: 30389923 PMCID: PMC6214970 DOI: 10.1038/s41467-018-06949-w] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2018] [Accepted: 08/02/2018] [Indexed: 11/09/2022] Open
Abstract
Activation of platelet-derived growth factor receptor alpha (PDGFRA) by genomic aberrations contributes to tumor progression in several tumor types. In this study, we characterize 16 novel PDGFRA mutations identified from different tumor types and identify three previously uncharacterized activating mutations that promote cell survival and proliferation. PDGFRA Y288C, an extracellular domain mutation, is primarily high mannose glycosylated consistent with trapping in the endoplasmic reticulum (ER). Strikingly, PDGFRA Y288C is constitutively dimerized and phosphorylated in the absence of ligand suggesting that trapping in the ER or aberrant glycosylation is sufficient for receptor activation. Importantly, PDGFRA Y288C induces constitutive phosphorylation of Akt, ERK1/2, and STAT3. PDGFRA Y288C is resistant to PDGFR inhibitors but sensitive to PI3K/mTOR and MEK inhibitors consistent with pathway activation results. Our findings further highlight the importance of characterizing functional consequences of individual mutations for precision medicine.
Collapse
Affiliation(s)
- Carman K M Ip
- Department of Systems Biology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, 77030, USA.
| | - Patrick K S Ng
- Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, 77030, USA
| | - Kang Jin Jeong
- Department of Systems Biology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, 77030, USA
| | - S H Shao
- Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, 77030, USA
| | - Zhenlin Ju
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, 77030, USA
| | - P G Leonard
- Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, 1881 East Road, Houston, TX, 77054, USA.,Core for Biomolecular Structure and Function, Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, 1881 East Road, Houston, TX, 77054, USA
| | - Xu Hua
- Department of Systems Biology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, 77030, USA
| | - Christopher P Vellano
- Center for Co-Clinical Trials, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Richard Woessner
- Cancer Bioscience, in vivo Cancer Pharmacology, AstraZeneca Phamaceuticals, Boston, MA, 02451, USA
| | - Nidhi Sahni
- Department of Systems Biology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, 77030, USA.,Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, 1808 Park Rd 1C, Smithville, TX, 78957, USA
| | - Kenneth L Scott
- Dan L. Duncan Cancer Center, Baylor College of Medicine, One Baylor Plaza, Suite 450A, Houston, TX, 77030, USA
| | - Gordon B Mills
- Department of Systems Biology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, 77030, USA.,Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, 77030, USA
| |
Collapse
|
|
28
|
Shen M, Kang Y. Complex interplay between tumor microenvironment and cancer therapy. Front Med 2018; 12:426-439. [PMID: 30097962 DOI: 10.1007/s11684-018-0663-7] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2018] [Accepted: 07/05/2018] [Indexed: 12/16/2022]
Abstract
Tumor microenvironment (TME) is comprised of cellular and non-cellular components that exist within and around the tumor mass. The TME is highly dynamic and its importance in different stages of cancer progression has been well recognized. A growing body of evidence suggests that TME also plays pivotal roles in cancer treatment responses. TME is significantly remodeled upon cancer therapies, and such change either enhances the responses or induces drug resistance. Given the importance of TME in tumor progression and therapy resistance, strategies that remodel TME to improve therapeutic responses are under developing. In this review, we provide an overview of the essential components in TME and the remodeling of TME in response to anti-cancer treatments. We also summarize the strategies that aim to enhance therapeutic efficacy by modulating TME.
Collapse
Affiliation(s)
- Minhong Shen
- Department of Molecular Biology, Princeton University, Princeton, NJ, 08544, USA
| | - Yibin Kang
- Department of Molecular Biology, Princeton University, Princeton, NJ, 08544, USA.
| |
Collapse
|
|
29
|
Cheriyan VT, Alsaab H, Sekhar S, Venkatesh J, Mondal A, Vhora I, Sau S, Muthu M, Polin LA, Levi E, Bepler G, Iyer AK, Singh M, Rishi AK. A CARP-1 functional mimetic compound is synergistic with BRAF-targeting in non-small cell lung cancers. Oncotarget 2018; 9:29680-29697. [PMID: 30038713 PMCID: PMC6049854 DOI: 10.18632/oncotarget.25671] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2018] [Accepted: 05/15/2018] [Indexed: 02/07/2023] Open
Abstract
Non-small cell lung cancers (NSCLC) account for 85% of all lung cancers, and the epidermal growth factor receptor (EGFR) is highly expressed or activated in many NSCLC that permit use of EGFR tyrosine kinase inhibitors (TKIs) as frontline therapies. Resistance to EGFR TKIs eventually develops that necessitates development of improved and effective therapeutics. CARP-1/CCAR1 is an effector of apoptosis by Doxorubicin, Etoposide, or Gefitinib, while CARP-1 functional mimetic (CFM) compounds bind with CARP-1, and stimulate CARP-1 expression and apoptosis. To test whether CFMs would inhibit TKI-resistant NSCLCs, we first generated and characterized TKI-resistant NSCLC cells. The GI50 dose of Erlotinib for parental and Erlotinib-resistant HCC827 cells was ∼0.1 μM and ≥15 μM, respectively. While Rociletinib or Ocimertinib inhibited the parental H1975 cells with GI50 doses of ≤0.18 μM, the Ocimertinib-resistant pools of H1975 cells had a GI50 dose of ∼12 μM. The GI50 dose for Rociletinib-resistant H1975 sublines ranged from 4.5-8.0 μM. CFM-4 and its novel analog CFM-4.16 attenuated growth of the parental and TKI-resistant NSCLC cells. CFMs activated p38/JNKs, inhibited oncogenic cMet and Akt kinases, while CARP-1 depletion blocked NSCLC cell growth inhibition by CFM-4.16 or Erlotinib. CFM-4.16 was synergistic with B-Raf-targeting in NSCLC, triple-negative breast cancer, and renal cancer cells. A nano-lipid formulation (NLF) of CFM-4.16 in combination with Sorafenib elicited a superior growth inhibition of xenografted tumors derived from Rociletinib-resistant H1975 NSCLC cells in part by stimulating CARP-1 and apoptosis. These findings support therapeutic potential of CFM-4.16 together with B-Raf targeting in treatment of TKI-resistant NSCLCs.
Collapse
Affiliation(s)
- Vino T Cheriyan
- John D. Dingell VA Medical Center, Detroit, MI, 48201, USA.,Department of Oncology, Barbara Ann Karmanos Cancer Institute, Wayne State University, School of Medicine, Detroit, MI, 48201, USA
| | - Hashem Alsaab
- Use-inspired Biomaterials and Integrated Nano Delivery (U-BiND) Systems Laboratory Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI 48201, USA.,Department of Pharmaceutics and Pharmaceutical Technology, College of Pharmacy, Taif University, Taif 26571, Saudi Arabia
| | - Sreeja Sekhar
- John D. Dingell VA Medical Center, Detroit, MI, 48201, USA.,Department of Oncology, Barbara Ann Karmanos Cancer Institute, Wayne State University, School of Medicine, Detroit, MI, 48201, USA
| | - Jaganathan Venkatesh
- John D. Dingell VA Medical Center, Detroit, MI, 48201, USA.,Department of Oncology, Barbara Ann Karmanos Cancer Institute, Wayne State University, School of Medicine, Detroit, MI, 48201, USA
| | - Arindam Mondal
- College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL 32307, USA
| | - Imran Vhora
- College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL 32307, USA
| | - Samaresh Sau
- Use-inspired Biomaterials and Integrated Nano Delivery (U-BiND) Systems Laboratory Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI 48201, USA
| | - Magesh Muthu
- John D. Dingell VA Medical Center, Detroit, MI, 48201, USA.,Department of Oncology, Barbara Ann Karmanos Cancer Institute, Wayne State University, School of Medicine, Detroit, MI, 48201, USA.,Present Address: Department of Molecular Biology, Umeå University, Umeå 90187, Sweden
| | - Lisa A Polin
- Department of Oncology, Barbara Ann Karmanos Cancer Institute, Wayne State University, School of Medicine, Detroit, MI, 48201, USA.,Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Wayne State University, School of Medicine, Detroit, MI, 48201, USA
| | - Edi Levi
- John D. Dingell VA Medical Center, Detroit, MI, 48201, USA.,Department of Pathology, Wayne State University, School of Medicine, Detroit, MI, 48201, USA
| | - Gerold Bepler
- Department of Oncology, Barbara Ann Karmanos Cancer Institute, Wayne State University, School of Medicine, Detroit, MI, 48201, USA
| | - Arun K Iyer
- Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Wayne State University, School of Medicine, Detroit, MI, 48201, USA.,Use-inspired Biomaterials and Integrated Nano Delivery (U-BiND) Systems Laboratory Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI 48201, USA
| | - Mandip Singh
- College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL 32307, USA
| | - Arun K Rishi
- John D. Dingell VA Medical Center, Detroit, MI, 48201, USA.,Department of Oncology, Barbara Ann Karmanos Cancer Institute, Wayne State University, School of Medicine, Detroit, MI, 48201, USA.,Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Wayne State University, School of Medicine, Detroit, MI, 48201, USA
| |
Collapse
|
|
30
|
Crosstalk between cancer cells and endothelial cells: implications for tumor progression and intervention. Arch Pharm Res 2018; 41:711-724. [DOI: 10.1007/s12272-018-1051-1] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2018] [Accepted: 06/26/2018] [Indexed: 02/07/2023]
|
|
31
|
Molnár E, Rittler D, Baranyi M, Grusch M, Berger W, Döme B, Tóvári J, Aigner C, Tímár J, Garay T, Hegedűs B. Pan-RAF and MEK vertical inhibition enhances therapeutic response in non-V600 BRAF mutant cells. BMC Cancer 2018; 18:542. [PMID: 29739364 PMCID: PMC5941622 DOI: 10.1186/s12885-018-4455-x] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2017] [Accepted: 04/30/2018] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Currently, there are no available targeted therapy options for non-V600 BRAF mutated tumors. The aim of this study was to investigate the effects of RAF and MEK concurrent inhibition on tumor growth, migration, signaling and apoptosis induction in preclinical models of non-V600 BRAF mutant tumor cell lines. METHODS Six BRAF mutated human tumor cell lines CRL5885 (G466 V), WM3629 (D594G), WM3670 (G469E), MDAMB231 (G464 V), CRL5922 (L597 V) and A375 (V600E as control) were investigated. Pan-RAF inhibitor (sorafenib or AZ628) and MEK inhibitor (selumetinib) or their combination were used in in vitro viability, video microscopy, immunoblot, cell cycle and TUNEL assays. The in vivo effects of the drugs were assessed in an orthotopic NSG mouse breast cancer model. RESULTS All cell lines showed a significant growth inhibition with synergism in the sorafenib/AZ628 and selumetinib combination. Combination treatment resulted in higher Erk1/2 inhibition and in increased induction of apoptosis when compared to single agent treatments. However, single selumetinib treatment could cause adverse therapeutic effects, like increased cell migration in certain cells, selumetinib and sorafenib combination treatment lowered migratory capacity in all the cell lines. Importantly, combination resulted in significantly increased tumor growth inhibition in orthotropic xenografts of MDAMB231 cells when compared to sorafenib - but not to selumetinib - treatment. CONCLUSIONS Our data suggests that combined blocking of RAF and MEK may achieve increased therapeutic response in non-V600 BRAF mutant tumors.
Collapse
Affiliation(s)
- Eszter Molnár
- 2nd Department of Pathology, Semmelweis University, Budapest, 1091, Hungary
| | - Dominika Rittler
- 2nd Department of Pathology, Semmelweis University, Budapest, 1091, Hungary
| | - Marcell Baranyi
- 2nd Department of Pathology, Semmelweis University, Budapest, 1091, Hungary
| | - Michael Grusch
- Institute of Cancer Research, Medical University of Vienna, 1090, Vienna, Austria
| | - Walter Berger
- Institute of Cancer Research, Medical University of Vienna, 1090, Vienna, Austria
| | - Balázs Döme
- Department of Thoracic Surgery, Medical University of Vienna, 1090, Vienna, Austria.,National Korányi Institute of TB and Pulmonology, Budapest, 1085, Hungary.,Department of Thoracic Surgery, Semmelweis University-National Institute of Oncology, Budapest, 1122, Hungary
| | - József Tóvári
- Department of Experimental Pharmacology, National Institute of Oncology, Budapest, 1122, Hungary
| | - Clemens Aigner
- Department of Thoracic Surgery, Ruhrlandklinik, University Duisburg-Essen, 45239, Essen, Germany
| | - József Tímár
- 2nd Department of Pathology, Semmelweis University, Budapest, 1091, Hungary.,HAS-SE Molecular Oncology Research Group, Hungarian Academy of Sciences, Budapest, 1051, Hungary
| | - Tamás Garay
- 2nd Department of Pathology, Semmelweis University, Budapest, 1091, Hungary.,HAS-SE Molecular Oncology Research Group, Hungarian Academy of Sciences, Budapest, 1051, Hungary.,HAS Postdoctoral Fellowship Program Hungarian Academy of Sciences, Budapest, 1051, Hungary
| | - Balázs Hegedűs
- 2nd Department of Pathology, Semmelweis University, Budapest, 1091, Hungary. .,Department of Thoracic Surgery, Ruhrlandklinik, University Duisburg-Essen, 45239, Essen, Germany. .,HAS-SE Molecular Oncology Research Group, Hungarian Academy of Sciences, Budapest, 1051, Hungary.
| |
Collapse
|
|
32
|
Dragovich MA, Mor A. The SLAM family receptors: Potential therapeutic targets for inflammatory and autoimmune diseases. Autoimmun Rev 2018; 17:674-682. [PMID: 29729453 DOI: 10.1016/j.autrev.2018.01.018] [Citation(s) in RCA: 49] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2018] [Accepted: 01/18/2018] [Indexed: 12/20/2022]
Abstract
The signaling lymphocytic activation molecule (SLAM) family is comprised of nine distinct receptors (SLAMF1 through SLAMF9) that are expressed on hematopoietic cells. All of these receptors, with the exception of SLAMF4, are homotypic by nature as downstream signaling occurs when hematopoietic cells that express the same SLAM receptor interact. The SLAM family receptor function is largely controlled via SLAM associated protein (SAP) family adaptors. The SAP family adaptors consist of SAP, Ewing sarcoma associated transcript (EAT)-2, and EAT-2-related transducer (ERT). These adaptors associate with the cytoplasmic domain of the SLAM family receptors through phosphorylated tyrosines. Defects in SLAM family members and SAP adaptors have been implicated in causing immune deficiencies. This is exemplified in patients with X-linked lymphoproliferative (XLP) disease, where SAP undergoes a loss of function mutation. Furthermore, evidence has been accumulating that SLAM family members are potential targets for inflammatory and autoimmune diseases. This review will discuss the structure and function of the SLAM family receptors and SAP family adaptors, their role in immune regulation, and potential approaches to target this family of receptors therapeutically.
Collapse
Affiliation(s)
- Matthew A Dragovich
- Department of Medicine, Division of Rheumatology, NYU School of Medicine, New York, NY 10016, USA; Perlmutter Cancer Center, NYU School of Medicine, New York, NY 10016, USA
| | - Adam Mor
- Department of Medicine, Division of Rheumatology, NYU School of Medicine, New York, NY 10016, USA; Perlmutter Cancer Center, NYU School of Medicine, New York, NY 10016, USA.
| |
Collapse
|
|
33
|
Wang L, Zhao L, Wei G, Saur D, Seidler B, Wang J, Wang C, Qi T. Homoharringtonine could induce quick protein synthesis of PSMD11 through activating MEK1/ERK1/2 signaling pathway in pancreatic cancer cells. J Cell Biochem 2018; 119:6644-6656. [PMID: 29665121 DOI: 10.1002/jcb.26847] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2017] [Accepted: 09/09/2018] [Indexed: 02/01/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) remains one of the most devastating disease with the 5-year survival rate less than 6%. In this study, we investigated if inhibiting protein synthesis directly with homoharringtonine (HHT) could induce acute apoptosis in pancreatic cancer cells through quick depletion of multiple short-lived critical members of the central proteome, example, PSMD11(26S proteasome non-ATPase regulatory subunit 11). It was shown that although HHT could inhibit proliferation and growth of MiaPaCa-2 and PANC-1 cells in a time- and dose-dependent manner, only part of pancreatic cancer cells could be induced to die through acute apoptosis. Mechanistic studies showed that HHT could induce quick protein synthesis of PSMD11 through activating MEK1/ERK1/2 signaling pathway in pancreatic cancer cells. Inhibiting MEK1/ERK1/2 pathway with sorafenib could improve the cytotoxity of HHT in vitro and in a genetically engineered mouse model of pancreatic cancer. These results suggest that quick induction of PSMD11 or other acute apoptosis inhibitors through activation of the MEK1/ERK1/2 signaling pathway may be one of the important surviving mechanism which can help pancreatic cancer cells avoid acute apoptosis, it may have significant implications for the targeted therapy of pancreatic ductal adenocarcinoma.
Collapse
Affiliation(s)
- Lele Wang
- Central Research Laboratory, The Second Hospital of Shandong University, Jinan, China
| | - Linlin Zhao
- Central Research Laboratory, The Second Hospital of Shandong University, Jinan, China
| | - Guo Wei
- Department of Dermatology, The Second Hospital of Shandong University, Jinan, China
| | - Dieter Saur
- The II. Medizinische Klinik und Poliklinik der Technischen Universität München, München, Germany
| | - Barbara Seidler
- The II. Medizinische Klinik und Poliklinik der Technischen Universität München, München, Germany
| | - Junyan Wang
- Department of Internal Medicine, Dezhou People's Hospital, Dezhou, China
| | - Chuanxin Wang
- Central Research Laboratory, The Second Hospital of Shandong University, Jinan, China
| | - Tonggang Qi
- Central Research Laboratory, The Second Hospital of Shandong University, Jinan, China.,The Third People's Hospital of Tibet, Central Laboratory, Lhasa, China
| |
Collapse
|
|
34
|
Gong J, Cho M, Sy M, Salgia R, Fakih M. Molecular profiling of metastatic colorectal tumors using next-generation sequencing: a single-institution experience. Oncotarget 2018. [PMID: 28178681 DOI: 10.1158/0008-5472.can-15-3043.] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND Recent molecular characterization of colorectal tumors has identified several molecular alterations of interest that are considered targetable in metastatic colorectal cancer (mCRC). METHODS We conducted a single-institution, retrospective study based on comprehensive genomic profiling of tumors from 138 patients with mCRC using next-generation sequencing (NGS) via FoundationOne. RESULTS Overall, RAS mutations were present in 51.4% and RAF mutations were seen in 7.2% of mCRC patients. We found a novel KRASR68S1 mutation associated with an aggressive phenotype. RAS amplifications (1.4% KRAS and 0.7% NRAS), MET amplifications (2.2%), BRAFL597Ralterations (0.7%), ARAFS214F alterations (0.7%), and concurrent RAS+RAF (1.4%), BRAF+RAF1 (0.7%), and rare PTEN-PIK3CA-AKT pathway mutations were identified and predominantly associated with poor prognosis. ERBB2 (HER2) amplified tumors were identified in 5.1% and all arose from the rectosigmoid colon. Three cases (2.2%) were associated with a hypermutated profile that was corroborated with findings of high tumor mutational burden (TMB): 2 cases with MSI-H and 1 case with a POLE mutation. CONCLUSIONS Comprehensive genomic profiling can uncover alterations beyond the well-characterized RAS/RAF mutations associated with anti-EGFR resistance. ERBB2 amplified tumors commonly originate from the rectosigmoid colon, are predominantly RAS/BRAF wild-type, and may predict benefit to HER2-directed therapy. Hypermutant tumors or tumors with high TMB correlate with MSI-H status or POLE mutations and may predict a benefit from anti-PD-1 therapy.
Collapse
Affiliation(s)
- Jun Gong
- Department of Medical Oncology, City of Hope National Medical Center, Duarte, CA, USA
| | - May Cho
- Department of Medical Oncology, City of Hope National Medical Center, Duarte, CA, USA
| | - Marvin Sy
- Department of Medical Oncology, City of Hope National Medical Center, Duarte, CA, USA
| | - Ravi Salgia
- Department of Medical Oncology, City of Hope National Medical Center, Duarte, CA, USA
| | - Marwan Fakih
- Department of Medical Oncology, City of Hope National Medical Center, Duarte, CA, USA
| |
Collapse
|
|
35
|
Dankner M, Rose AAN, Rajkumar S, Siegel PM, Watson IR. Classifying BRAF alterations in cancer: new rational therapeutic strategies for actionable mutations. Oncogene 2018. [DOI: 10.1038/s41388-018-0171-x] [Citation(s) in RCA: 196] [Impact Index Per Article: 28.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
|
|
36
|
Toor OM, Ahmed Z, Bahaj W, Boda U, Cummings LS, McNally ME, Kennedy KF, Pluard TJ, Hussain A, Subramanian J, Masood A. Correlation of Somatic Genomic Alterations Between Tissue Genomics and ctDNA Employing Next-Generation Sequencing: Analysis of Lung and Gastrointestinal Cancers. Mol Cancer Ther 2018; 17:1123-1132. [PMID: 29500272 DOI: 10.1158/1535-7163.mct-17-1015] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2017] [Revised: 12/19/2017] [Accepted: 02/23/2018] [Indexed: 11/16/2022]
Abstract
Next-generation Sequencing (NGS) of cancer tissues is increasingly being carried out to identify somatic genomic alterations that may guide physicians to make therapeutic decisions. However, a single tissue biopsy may not reflect complete genomic architecture due to the heterogeneous nature of tumors. Circulating tumor DNA (ctDNA) analysis is a robust noninvasive method to detect and monitor genomic alterations in blood in real time. We analyzed 28 matched tissue NGS and ctDNA from gastrointestinal and lung cancers for concordance of somatic genomic alterations, driver, and actionable alterations. Six patients (21%) had at least one concordant mutation between tissue and ctDNA sequencing. At the gene level, among all the mutations (n = 104) detected by tissue and blood sequencing, 7.7% (n = 8) of mutations were concordant. Tissue and ctDNA sequencing identified driver mutations in 60% and 64% of the tested samples, respectively. We found high discordance between tissue and ctDNA testing, especially with respect to the driver and actionable alterations. Both tissue and ctDNA NGS detected actionable alterations in 25% of patients. When somatic alterations identified by each test were combined, the total number of patients with actionable mutations increased to 32%. Our data show significant discordance between tissue NGS and ctDNA analysis. These results suggest tissue NGS and ctDNA NGS are complementary approaches rather than exclusive of each other. When performed in isolation, tissue and ctDNA NGS can each potentially miss driver and targetable alterations, suggesting that both approaches should be incorporated to enhance mutation detection rates. Larger prospective studies are needed to better clarify this emerging precision oncology landscape. Mol Cancer Ther; 17(5); 1123-32. ©2018 AACR.
Collapse
Affiliation(s)
- Omer M Toor
- Department of Medicine, University of Missouri Kansas City School of Medicine, Kansas City, Missouri
- Center for Precision Oncology, Saint Luke's Cancer Institute, Kansas City, Missouri
| | - Zaheer Ahmed
- Department of Medicine, University of Missouri Kansas City School of Medicine, Kansas City, Missouri
| | - Waled Bahaj
- Department of Medicine, University of Missouri Kansas City School of Medicine, Kansas City, Missouri
| | - Urooge Boda
- Department of Medicine, University of Missouri Kansas City School of Medicine, Kansas City, Missouri
| | - Lee S Cummings
- Department of Surgery, University of Missouri Kansas City, Missouri
- Division of Hepatobiliary Surgery, Saint Luke's Hospital, Kansas City, Missouri
| | - Megan E McNally
- Division of Surgical Oncology, Saint Luke's Cancer Institute, Kansas City, Missouri
| | - Kevin F Kennedy
- Division of Cardiovascular Research, Saint Luke's Hospital, Kansas City, Missouri
| | - Timothy J Pluard
- Department of Medicine, University of Missouri Kansas City School of Medicine, Kansas City, Missouri
- Center for Precision Oncology, Saint Luke's Cancer Institute, Kansas City, Missouri
- Division of Oncology, Saint Luke's Cancer Institute, Kansas City, Missouri
| | - Arif Hussain
- Division of Oncology, University of Maryland Greenebaum Comprehensive Cancer Center, Baltimore, Maryland
- The Baltimore Veterans Affairs Medical Center, Baltimore, Maryland
| | - Janakiraman Subramanian
- Department of Medicine, University of Missouri Kansas City School of Medicine, Kansas City, Missouri
- Center for Precision Oncology, Saint Luke's Cancer Institute, Kansas City, Missouri
- Division of Oncology, Saint Luke's Cancer Institute, Kansas City, Missouri
| | - Ashiq Masood
- Department of Medicine, University of Missouri Kansas City School of Medicine, Kansas City, Missouri.
- Center for Precision Oncology, Saint Luke's Cancer Institute, Kansas City, Missouri
- Division of Oncology, Saint Luke's Cancer Institute, Kansas City, Missouri
| |
Collapse
|
|
37
|
Kim T, Havighurst T, Kim K, Albertini M, Xu YG, Spiegelman VS. Targeting insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) in metastatic melanoma to increase efficacy of BRAF V600E inhibitors. Mol Carcinog 2018; 57:678-683. [PMID: 29369405 DOI: 10.1002/mc.22786] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2017] [Revised: 01/10/2018] [Accepted: 01/22/2018] [Indexed: 01/18/2023]
Abstract
Melanoma is one of the deadliest forms of skin cancer. Although BRAF inhibitors significantly enhance survival of metastatic melanoma patients, most patients relapse after less than a year of treatment. We previously reported that mRNA binding protein Insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) is overexpressed in metastatic melanoma and that expression of IGF2BP1 confers resistance to chemotherapeutic agents. Here we demonstrate that IGF2BP1 plays an important role in the sensitivity of melanoma to targeted therapy. Inhibition of IGF2BP1 enhances the effects of BRAF-inhibitor and BRAF-MEK inhibitors in BRAFV600E melanoma. Also, knockdown of IGF2BP1 alone is sufficient to reduce tumorigenic characteristics in vemurafenib-resistant melanoma. These findings suggest that IGF2BP1 can be a novel therapeutic target for melanoma.
Collapse
Affiliation(s)
- TaeWon Kim
- Department of Dermatology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.,Molecular and Environmental Toxicology Center, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Thomas Havighurst
- Department of Biostatistics and Medical Informatics, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - KyungMann Kim
- Department of Biostatistics and Medical Informatics, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.,Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Mark Albertini
- Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.,Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.,Medical Service, William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin
| | - Yaohui G Xu
- Department of Dermatology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.,Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Vladimir S Spiegelman
- Department of Dermatology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.,Department of Pediatrics, Pennsylvania State University, Hershey, Pennsylvania
| |
Collapse
|
|
38
|
Jensen BC, Parry TL, Huang W, Beak JY, Ilaiwy A, Bain JR, Newgard CB, Muehlbauer MJ, Patterson C, Johnson GL, Willis MS. Effects of the kinase inhibitor sorafenib on heart, muscle, liver and plasma metabolism in vivo using non-targeted metabolomics analysis. Br J Pharmacol 2017; 174:4797-4811. [PMID: 28977680 PMCID: PMC5727336 DOI: 10.1111/bph.14062] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2017] [Revised: 09/11/2017] [Accepted: 09/25/2017] [Indexed: 12/27/2022] Open
Abstract
BACKGROUND AND PURPOSE The human kinome consists of roughly 500 kinases, including 150 that have been proposed as therapeutic targets. Protein kinases regulate an array of signalling pathways that control metabolism, cell cycle progression, cell death, differentiation and survival. It is not surprising, then, that new kinase inhibitors developed to treat cancer, including sorafenib, also exhibit cardiotoxicity. We hypothesized that sorafenib cardiotoxicity is related to its deleterious effects on specific cardiac metabolic pathways given the critical roles of protein kinases in cardiac metabolism. EXPERIMENTAL APPROACH FVB/N mice (10 per group) were challenged with sorafenib or vehicle control daily for 2 weeks. Echocardiographic assessment of the heart identified systolic dysfunction consistent with cardiotoxicity in sorafenib-treated mice compared to vehicle-treated controls. Heart, skeletal muscle, liver and plasma were flash frozen and prepped for non-targeted GC-MS metabolomics analysis. KEY RESULTS Compared to vehicle-treated controls, sorafenib-treated hearts exhibited significant alterations in 11 metabolites, including markedly altered taurine/hypotaurine metabolism (25-fold enrichment), identified by pathway enrichment analysis. CONCLUSIONS AND IMPLICATIONS These studies identified alterations in taurine/hypotaurine metabolism in the hearts and skeletal muscles of mice treated with sorafenib. Interventions that rescue or prevent these sorafenib-induced changes, such as taurine supplementation, may be helpful in attenuating sorafenib-induced cardiac injury.
Collapse
Affiliation(s)
- Brian C Jensen
- McAllister Heart InstituteUniversity of North CarolinaChapel HillNCUSA
- Department of Internal MedicineDivision of Cardiology University of North CarolinaChapel HillNCUSA
- Department of PharmacologyUniversity of North CarolinaChapel HillNCUSA
| | - Traci L Parry
- McAllister Heart InstituteUniversity of North CarolinaChapel HillNCUSA
- Department of Pathology & Laboratory MedicineUniversity of North CarolinaChapel HillNCUSA
| | - Wei Huang
- McAllister Heart InstituteUniversity of North CarolinaChapel HillNCUSA
| | - Ju Youn Beak
- McAllister Heart InstituteUniversity of North CarolinaChapel HillNCUSA
| | - Amro Ilaiwy
- Sarah W. Stedman Nutrition and Metabolism Center, Duke Molecular Physiology InstituteDuke University Medical CenterDurhamNCUSA
- Division of Endocrinology, Metabolism, and Nutrition, Department of MedicineDuke University Medical CenterDurhamNCUSA
| | - James R Bain
- Sarah W. Stedman Nutrition and Metabolism Center, Duke Molecular Physiology InstituteDuke University Medical CenterDurhamNCUSA
- Division of Endocrinology, Metabolism, and Nutrition, Department of MedicineDuke University Medical CenterDurhamNCUSA
| | - Christopher B Newgard
- Sarah W. Stedman Nutrition and Metabolism Center, Duke Molecular Physiology InstituteDuke University Medical CenterDurhamNCUSA
- Division of Endocrinology, Metabolism, and Nutrition, Department of MedicineDuke University Medical CenterDurhamNCUSA
| | - Michael J Muehlbauer
- Sarah W. Stedman Nutrition and Metabolism Center, Duke Molecular Physiology InstituteDuke University Medical CenterDurhamNCUSA
| | - Cam Patterson
- Presbyterian Hospital/Weill‐Cornell Medical CenterNew YorkNYUSA
| | - Gary L Johnson
- Department of PharmacologyUniversity of North CarolinaChapel HillNCUSA
| | - Monte S Willis
- McAllister Heart InstituteUniversity of North CarolinaChapel HillNCUSA
- Department of Pathology & Laboratory MedicineUniversity of North CarolinaChapel HillNCUSA
- Department of PharmacologyUniversity of North CarolinaChapel HillNCUSA
| |
Collapse
|
|
39
|
Xu X, Li N, Zhao R, Zhu L, Shao J, Zhang J. Targeted next-generation sequencing for analyzing the genetic alterations in atypical adenomatous hyperplasia and adenocarcinoma in situ. J Cancer Res Clin Oncol 2017; 143:2447-2453. [PMID: 28821955 DOI: 10.1007/s00432-017-2500-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2017] [Accepted: 08/10/2017] [Indexed: 01/04/2023]
Abstract
PURPOSE Atypical adenomatous hyperplasia (AAH) and adenocarcinoma in situ (AIS) have been defined as preinvasive pulmonary adenocarcinoma lesions according to the 2015 World Health Organization lung adenocarcinoma classification. We aimed to search for the most common gene mutations in patients with AAH and AIS and investigate the distinctions between the two groups at the molecular level. METHODS We performed targeted next-generation sequencing on 18 cases with AAH and 28 cases with AIS to screen for mutations with the Ion Torrent Oncomine Solid Tumor DNA panel. ALK and ROS1 fusions were detected by real-time PCR. RESULTS Forty-six mutations were identified in 29 cases (76.1%), including 9 (50%) of 18 cases with AAH and 20 (71.4%) of 28 cases with AIS, in the following genes: EGFR, BRAF, KRAS, ERBB2, TP53, and FGFR3. The mutations in EGFR, BRAF, KRAS, ERBB2, and TP53 genes were more common in AIS lesions than in AAH lesions, whereas the FGFR3 gene was more frequently mutated in AAH compared to AIS. ALK and ROS1 fusions were not detected in any of the lesions. CONCLUSIONS Based on the molecular evidence, the proposal that AAH and AIS are preinvasive lesions of pulmonary adenocarcinomas is of great significance, and it is necessary to distinguish AAH from AIS. Our study provided insights into the genetic alterations in the early stage of lung adenocarcinoma, which could be beneficial for the pathologic diagnosis and early detection of these lesions.
Collapse
Affiliation(s)
- Xuan Xu
- Department of Pathology, Shanghai Chest Hospital, Shanghai Jiao Tong University, 241 West Huaihai Road, Shanghai, 200030, China
| | - Na Li
- Department of Pathology, Shanghai Chest Hospital, Shanghai Jiao Tong University, 241 West Huaihai Road, Shanghai, 200030, China
| | - Ruiying Zhao
- Department of Pathology, Shanghai Chest Hospital, Shanghai Jiao Tong University, 241 West Huaihai Road, Shanghai, 200030, China
| | - Lei Zhu
- Department of Pathology, Shanghai Chest Hospital, Shanghai Jiao Tong University, 241 West Huaihai Road, Shanghai, 200030, China
| | - Jinchen Shao
- Department of Pathology, Shanghai Chest Hospital, Shanghai Jiao Tong University, 241 West Huaihai Road, Shanghai, 200030, China
| | - Jie Zhang
- Department of Pathology, Shanghai Chest Hospital, Shanghai Jiao Tong University, 241 West Huaihai Road, Shanghai, 200030, China.
| |
Collapse
|
|
40
|
Bad phosphorylation as a target of inhibition in oncology. Cancer Lett 2017; 415:177-186. [PMID: 29175460 DOI: 10.1016/j.canlet.2017.11.017] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2017] [Revised: 11/13/2017] [Accepted: 11/17/2017] [Indexed: 12/19/2022]
Abstract
Bcl-2 agonist of cell death (BAD) is a BH3-only member of the Bcl-2 family which possesses important regulatory function in apoptosis. BAD has also been shown to possess many non-apoptotic functions closely linked to cancer including regulation of glycolysis, autophagy, cell cycle progression and immune system development. Interestingly, BAD can be either pro-apoptotic or pro-survival depending on the phosphorylation state of three specific serine residues (human S75, S99 and S118). Expression of BAD and BAD phosphorylation patterns have been shown to influence tumor initiation and progression and play a predictive role in disease prognosis, drug response and chemosensitivity in various cancers. This review aims to summarize the current evidence on the functional role of BAD phosphorylation in human cancer and evaluate the potential utility of modulating BAD phosphorylation in cancer.
Collapse
|
|
41
|
Illei PB, Belchis D, Tseng LH, Nguyen D, De Marchi F, Haley L, Riel S, Beierl K, Zheng G, Brahmer JR, Askin FB, Gocke CD, Eshleman JR, Forde PM, Lin MT. Clinical mutational profiling of 1006 lung cancers by next generation sequencing. Oncotarget 2017; 8:96684-96696. [PMID: 29228562 PMCID: PMC5722514 DOI: 10.18632/oncotarget.18042] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2017] [Accepted: 05/10/2017] [Indexed: 12/15/2022] Open
Abstract
Analysis of lung adenocarcinomas for actionable mutations has become standard of care. Here, we report our experience using next generation sequencing (NGS) to examine AKT1, BRAF, EGFR, ERBB2, KRAS, NRAS, and PIK3CA genes in 1006 non-small cell lung cancers in a clinical diagnostic setting. NGS demonstrated high sensitivity. Among 760 mutations detected, the variant allele frequency (VAF) was 2-5% in 33 (4.3%) mutations and 2-10% in 101 (13%) mutations. A single bioinformatics pipeline using Torrent Variant Caller, however, missed a variety of EGFR mutations. Mutations were detected in KRAS (36% of tumors), EGFR (19%) including 8 (0.8%) within the extracellular domain (4 at codons 108 and 4 at codon 289), BRAF (6.3%), and PIK3CA (3.7%). With a broader reportable range, exon 19 deletion and p.L858R accounted for only 36% and 26% of EGFR mutations and p.V600E accounted for only 24% of BRAF mutations. NGS provided accurate sequencing of complex mutations seen in 19% of EGFR exon 19 deletion mutations. Doublet (compound) EGFR mutations were observed in 29 (16%) of 187 EGFR-mutated tumors, including 69% with two non-p.L858R missense mutations and 24% with p.L858 and non-p.L858R missense mutations. Concordant VAFs suggests doublet EGFR mutations were present in a dominant clone and cooperated in oncogenesis. Mutants with predicted impaired kinase, observed in 25% of BRAF-mutated tumors, were associated with a higher incidence of concomitant activating KRAS mutations. NGS demonstrates high analytic sensitivity, broad reportable range, quantitative VAF measurement, single molecule sequencing to resolve complex deletion mutations, and simultaneous detection of concomitant mutations.
Collapse
Affiliation(s)
- Peter B. Illei
- Department of Pathology, Johns Hopkins University School of Medicine, Johns Hopkins Hospital, Baltimore, Maryland, USA
| | - Deborah Belchis
- Department of Pathology, Johns Hopkins University School of Medicine, Johns Hopkins Hospital, Baltimore, Maryland, USA
| | - Li-Hui Tseng
- Department of Pathology, Johns Hopkins University School of Medicine, Johns Hopkins Hospital, Baltimore, Maryland, USA
- Department of Medical Genetics, National Taiwan University Hospital, Taipei, Taiwan
| | - Doreen Nguyen
- Department of Pathology, Johns Hopkins University School of Medicine, Johns Hopkins Hospital, Baltimore, Maryland, USA
| | - Federico De Marchi
- Department of Pathology, Johns Hopkins University School of Medicine, Johns Hopkins Hospital, Baltimore, Maryland, USA
- Division of Hematology and Bone Marrow Transplantation, University of Udine Hospital, Udine, Italy
| | - Lisa Haley
- Department of Pathology, Johns Hopkins University School of Medicine, Johns Hopkins Hospital, Baltimore, Maryland, USA
| | - Stacy Riel
- Department of Pathology, Johns Hopkins University School of Medicine, Johns Hopkins Hospital, Baltimore, Maryland, USA
| | - Katie Beierl
- Department of Pathology, Johns Hopkins University School of Medicine, Johns Hopkins Hospital, Baltimore, Maryland, USA
| | - Gang Zheng
- Department of Pathology, Johns Hopkins University School of Medicine, Johns Hopkins Hospital, Baltimore, Maryland, USA
| | - Julie R. Brahmer
- Department of Oncology, Johns Hopkins University School of Medicine, Johns Hopkins Hospital, Baltimore, Maryland, USA
| | - Frederic B. Askin
- Department of Pathology, Johns Hopkins University School of Medicine, Johns Hopkins Hospital, Baltimore, Maryland, USA
| | - Christopher D. Gocke
- Department of Pathology, Johns Hopkins University School of Medicine, Johns Hopkins Hospital, Baltimore, Maryland, USA
- Department of Oncology, Johns Hopkins University School of Medicine, Johns Hopkins Hospital, Baltimore, Maryland, USA
| | - James R. Eshleman
- Department of Pathology, Johns Hopkins University School of Medicine, Johns Hopkins Hospital, Baltimore, Maryland, USA
- Department of Oncology, Johns Hopkins University School of Medicine, Johns Hopkins Hospital, Baltimore, Maryland, USA
| | - Patrick M. Forde
- Department of Oncology, Johns Hopkins University School of Medicine, Johns Hopkins Hospital, Baltimore, Maryland, USA
| | - Ming-Tseh Lin
- Department of Pathology, Johns Hopkins University School of Medicine, Johns Hopkins Hospital, Baltimore, Maryland, USA
| |
Collapse
|
|
42
|
Uncommon BRAF Mutations Associated with Durable Response to Immunotherapy in Patients with Metastatic Melanoma. Case Rep Oncol Med 2017; 2017:8241624. [PMID: 29181212 PMCID: PMC5664253 DOI: 10.1155/2017/8241624] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2017] [Accepted: 08/23/2017] [Indexed: 12/13/2022] Open
Abstract
Melanoma is a disease process which has been increasing in incidence over the past three decades and metastatic melanoma carries a poor prognosis. Through genetic studies of this disease, it has been determined that the BRAF V600 mutation plays a major role in the pathophysiology of the disease and this has led to the utilization of targeted therapy (BRAF and MEK inhibitors) in its treatment. Other BRAF mutations (non-V600 mutations) are rare in melanoma and targeted therapy is not indicated for patients with these mutations due to reduced response rates. An emerging option for metastatic melanoma with uncommon BRAF mutations is immunotherapy using checkpoint inhibitors such as PD-1 inhibitors or CTLA-4 inhibitors. Currently, it is unknown how patients with BRAF non-V600 mutations respond to immunotherapy. This report will examine the effect of immunotherapy on two distinct metastatic melanoma patients, each with uncommon BRAF mutations, occurring outside the V600 locus (E586K and G469E). These patients were noted to have a durable, complete response when treated with immunotherapy and continue to exhibit a response 9 and 15 months after discontinuing therapy. Further research and clinical trials are needed to study patients with uncommon BRAF mutations and the potential therapeutic benefit of immunotherapy.
Collapse
|
|
43
|
Richtig G, Hoeller C, Kashofer K, Aigelsreiter A, Heinemann A, Kwong L, Pichler M, Richtig E. Beyond the BRAF
V
600E
hotspot: biology and clinical implications of rare BRAF
gene mutations in melanoma patients. Br J Dermatol 2017; 177:936-944. [DOI: 10.1111/bjd.15436] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/01/2017] [Indexed: 12/15/2022]
Affiliation(s)
- G. Richtig
- Institute of Experimental and Clinical Pharmacology; Medical University of Graz; Graz Austria
- Department of Dermatology; Medical University of Graz; Graz Austria
| | - C. Hoeller
- Department of Dermatology; Medical University of Vienna; Vienna Austria
| | - K. Kashofer
- Institute for Pathology; Medical University of Graz; Graz Austria
| | - A. Aigelsreiter
- Institute for Pathology; Medical University of Graz; Graz Austria
| | - A. Heinemann
- Institute of Experimental and Clinical Pharmacology; Medical University of Graz; Graz Austria
| | - L.N. Kwong
- Translational Molecular Pathology; The University of Texas MD Anderson Cancer Center; Houston TX U.S.A
| | - M. Pichler
- Division of Oncology; Medical University of Graz; Graz Austria
- Department of Experimental Therapeutics; The University of Texas MD Anderson Cancer Center; Houston TX U.S.A
| | - E. Richtig
- Department of Dermatology; Medical University of Graz; Graz Austria
| |
Collapse
|
|
44
|
Richtig G, Richtig E, Kashofer K, Koch L, Winter G, Hoefler G, Pichler M, Ehall B, Grübler MR, Heinemann A, Aigelsreiter A. Testing and clinical implications for non-V600 BRAF mutations in metastatic NRAS mt melanoma. Br J Dermatol 2017; 177:860-861. [PMID: 27925152 DOI: 10.1111/bjd.15222] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Affiliation(s)
- G Richtig
- Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria.,Department of Dermatology, Medical University of Graz, Graz, Austria
| | - E Richtig
- Department of Dermatology, Medical University of Graz, Graz, Austria
| | - K Kashofer
- Institute of Pathology, Medical University of Graz, Graz, Austria
| | - L Koch
- Department of Dermatology, Medical University of Graz, Graz, Austria
| | - G Winter
- Institute of Pathology, Medical University of Graz, Graz, Austria
| | - G Hoefler
- Institute of Pathology, Medical University of Graz, Graz, Austria
| | - M Pichler
- Division of Oncology, Medical University of Graz, Graz, Austria
| | - B Ehall
- Institute of Pathology, Medical University of Graz, Graz, Austria
| | - M R Grübler
- Swiss Cardiovascular Center Bern, Department of Cardiology, Bern University Hospital, Bern, Switzerland.,Department of Internal Medicine (Division of Endocrinology and Diabetology), Medical University of Graz, Graz, Austria
| | - A Heinemann
- Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria
| | - A Aigelsreiter
- Institute of Pathology, Medical University of Graz, Graz, Austria
| |
Collapse
|
|
45
|
Wu X, Yan J, Dai J, Ma M, Tang H, Yu J, Xu T, Yu H, Si L, Chi Z, Sheng X, Cui C, Kong Y, Guo J. Mutations in BRAF codons 594 and 596 predict good prognosis in melanoma. Oncol Lett 2017; 14:3601-3605. [PMID: 28927118 PMCID: PMC5587919 DOI: 10.3892/ol.2017.6608] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2017] [Accepted: 06/27/2017] [Indexed: 01/04/2023] Open
Abstract
B-Raf proto-oncogene serine/threonine kinase (BRAF) V600E is the most common kinase-activating mutation and is associated with poor prognosis in melanoma. However, the clinical significance of kinase-impairing mutations remains unclear. The present study aimed to analyze kinase-impairing mutations in BRAF codons 594 and 596 in non-Caucasian patients with melanoma and to investigate their possible clinical significance. To detect hotspot mutations, exon 15 of the BRAF gene was amplified using polymerase chain reaction in samples from 1,554 patients with melanoma. Among these patients, a total of 912 valid follow-up data were obtained. These patients were divided into three groups according to their BRAF activation status: BRAF wild-type (n=752), BRAF V600E (n=147); and BRAF D594/G596 (n=13). Then the correlation between BRAF activation status, and the clinicopathological features and overall survival (OS) of the patients were analyzed. The prevalence of BRAF mutations in non-Caucasian patients with melanoma was 24.3% (377/1554). Three patients carried two mutations simultaneously. The overall mutation frequencies of kinase-activating mutations, kinase-impairing mutations, and mutations with unknown effects were 93.4 (355/380), 3.4 (13/380), and 3.2% (12/380), respectively. BRAF V600E was identified to be associated with a poor prognosis. Patients with BRAF mutations in codons 594 and 596 had a longer OS time compared with those with a BRAF V600E mutation [median OS, 45 vs. 25 months; HR, 0.45 (95% confidence interval, 0.31-0.97); P=0.043]. To the best of our knowledge, this is the first study to examine a large number of samples from non-Caucasian patients with melanoma and report the characteristics of BRAF mutations according to mutant kinase activity. Melanoma arising from a mutation in BRAF codon 594 or 596 can be differentiated from BRAF V600E-induced melanoma, and mutations in these codons may be good prognostic factors for melanoma. The results of the present study are thus of significance for the development of accurate personalized medicine to treat melanoma.
Collapse
Affiliation(s)
- Xiaowen Wu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Renal Cancer and Melanoma, Peking University Cancer Hospital and Institute, Beijing 100142, P.R. China
| | - Junya Yan
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Renal Cancer and Melanoma, Peking University Cancer Hospital and Institute, Beijing 100142, P.R. China
| | - Jie Dai
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Renal Cancer and Melanoma, Peking University Cancer Hospital and Institute, Beijing 100142, P.R. China
| | - Meng Ma
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Renal Cancer and Melanoma, Peking University Cancer Hospital and Institute, Beijing 100142, P.R. China
| | - Huan Tang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Renal Cancer and Melanoma, Peking University Cancer Hospital and Institute, Beijing 100142, P.R. China
| | - Jiayi Yu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Renal Cancer and Melanoma, Peking University Cancer Hospital and Institute, Beijing 100142, P.R. China
| | - Tianxiao Xu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Renal Cancer and Melanoma, Peking University Cancer Hospital and Institute, Beijing 100142, P.R. China
| | - Huan Yu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Renal Cancer and Melanoma, Peking University Cancer Hospital and Institute, Beijing 100142, P.R. China
| | - Lu Si
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Renal Cancer and Melanoma, Peking University Cancer Hospital and Institute, Beijing 100142, P.R. China
| | - Zhihong Chi
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Renal Cancer and Melanoma, Peking University Cancer Hospital and Institute, Beijing 100142, P.R. China
| | - Xinan Sheng
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Renal Cancer and Melanoma, Peking University Cancer Hospital and Institute, Beijing 100142, P.R. China
| | - Chuanliang Cui
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Renal Cancer and Melanoma, Peking University Cancer Hospital and Institute, Beijing 100142, P.R. China
| | - Yan Kong
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Renal Cancer and Melanoma, Peking University Cancer Hospital and Institute, Beijing 100142, P.R. China
| | - Jun Guo
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Renal Cancer and Melanoma, Peking University Cancer Hospital and Institute, Beijing 100142, P.R. China
| |
Collapse
|
|
46
|
Galun D, Srdic-Rajic T, Bogdanovic A, Loncar Z, Zuvela M. Targeted therapy and personalized medicine in hepatocellular carcinoma: drug resistance, mechanisms, and treatment strategies. J Hepatocell Carcinoma 2017; 4:93-103. [PMID: 28744453 PMCID: PMC5513853 DOI: 10.2147/jhc.s106529] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is characterized by a growing number of new cases diagnosed each year that is nearly equal to the number of deaths from this cancer. In a majority of the cases, HCC is associated with the underlying chronic liver disease, and it is diagnosed in advanced stage of disease when curative treatment options are not applicable. Sorafenib is a treatment of choice for patients with performance status 1 or 2 and/or macrovascular invasion or extrahepatic spread, and regorafenib is the only systemic treatment found to provide survival benefit in HCC patients progressing on sorafenib treatment. Other drugs tested in different trials failed to demonstrate any benefit. Disappointing results of numerous trials testing the efficacy of various drugs indicate that HCC has low sensitivity to chemotherapy that is in great part caused by multidrug resistance. Immunotherapy for HCC is a new challenging treatment option and involves immune checkpoint inhibitors/antibody-based therapy and peptide-based vaccines. Another challenging approach is microRNA-based therapy that involves two strategies. The first aims to inhibit oncogenic miRNAs by using miRNA antagonists and the second strategy is miRNA replacement, which involves the reintroduction of a tumor-suppressor miRNA mimetic to restore a loss of function.
Collapse
Affiliation(s)
- Danijel Galun
- Hepato-Pancreato-Biliary Unit, University Clinic for Digestive Surgery, Clinical Center of Serbia
- Medical School, University of Belgrade
| | - Tatjana Srdic-Rajic
- Institute for Oncology and Radiology of Serbia/Unit for Experimental Oncology
| | - Aleksandar Bogdanovic
- Hepato-Pancreato-Biliary Unit, University Clinic for Digestive Surgery, Clinical Center of Serbia
| | - Zlatibor Loncar
- Medical School, University of Belgrade
- Emergency Center, Clinical Center of Serbia, Belgrade, Serbia
| | - Marinko Zuvela
- Hepato-Pancreato-Biliary Unit, University Clinic for Digestive Surgery, Clinical Center of Serbia
- Medical School, University of Belgrade
| |
Collapse
|
|
47
|
Gong J, Cho M, Sy M, Salgia R, Fakih M. Molecular profiling of metastatic colorectal tumors using next-generation sequencing: a single-institution experience. Oncotarget 2017; 8:42198-42213. [PMID: 28178681 PMCID: PMC5522060 DOI: 10.18632/oncotarget.15030] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2016] [Accepted: 01/16/2017] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Recent molecular characterization of colorectal tumors has identified several molecular alterations of interest that are considered targetable in metastatic colorectal cancer (mCRC). METHODS We conducted a single-institution, retrospective study based on comprehensive genomic profiling of tumors from 138 patients with mCRC using next-generation sequencing (NGS) via FoundationOne. RESULTS Overall, RAS mutations were present in 51.4% and RAF mutations were seen in 7.2% of mCRC patients. We found a novel KRASR68S1 mutation associated with an aggressive phenotype. RAS amplifications (1.4% KRAS and 0.7% NRAS), MET amplifications (2.2%), BRAFL597Ralterations (0.7%), ARAFS214F alterations (0.7%), and concurrent RAS+RAF (1.4%), BRAF+RAF1 (0.7%), and rare PTEN-PIK3CA-AKT pathway mutations were identified and predominantly associated with poor prognosis. ERBB2 (HER2) amplified tumors were identified in 5.1% and all arose from the rectosigmoid colon. Three cases (2.2%) were associated with a hypermutated profile that was corroborated with findings of high tumor mutational burden (TMB): 2 cases with MSI-H and 1 case with a POLE mutation. CONCLUSIONS Comprehensive genomic profiling can uncover alterations beyond the well-characterized RAS/RAF mutations associated with anti-EGFR resistance. ERBB2 amplified tumors commonly originate from the rectosigmoid colon, are predominantly RAS/BRAF wild-type, and may predict benefit to HER2-directed therapy. Hypermutant tumors or tumors with high TMB correlate with MSI-H status or POLE mutations and may predict a benefit from anti-PD-1 therapy.
Collapse
Affiliation(s)
- Jun Gong
- Department of Medical Oncology, City of Hope National Medical Center, Duarte, CA, USA
| | - May Cho
- Department of Medical Oncology, City of Hope National Medical Center, Duarte, CA, USA
| | - Marvin Sy
- Department of Medical Oncology, City of Hope National Medical Center, Duarte, CA, USA
| | - Ravi Salgia
- Department of Medical Oncology, City of Hope National Medical Center, Duarte, CA, USA
| | - Marwan Fakih
- Department of Medical Oncology, City of Hope National Medical Center, Duarte, CA, USA
| |
Collapse
|
|
48
|
Van Cutsem E, Dekervel J. Not All BRAF-Mutant Metastatic Colorectal Cancers Are Identical: Distinct Clinical Consequences of non-V600 BRAF Mutations. J Clin Oncol 2017; 35:2598-2599. [PMID: 28510493 DOI: 10.1200/jco.2017.72.7057] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Affiliation(s)
- Eric Van Cutsem
- Eric Van Cutsem and Jeroen Dekervel, University Hospitals Leuven and KULeuven, Leuven, Belgium
| | - Jeroen Dekervel
- Eric Van Cutsem and Jeroen Dekervel, University Hospitals Leuven and KULeuven, Leuven, Belgium
| |
Collapse
|
|
49
|
Xu J, Pfarr N, Endris V, Mai EK, Md Hanafiah NH, Lehners N, Penzel R, Weichert W, Ho AD, Schirmacher P, Goldschmidt H, Andrulis M, Raab MS. Molecular signaling in multiple myeloma: association of RAS/RAF mutations and MEK/ERK pathway activation. Oncogenesis 2017; 6:e337. [PMID: 28504689 PMCID: PMC5523069 DOI: 10.1038/oncsis.2017.36] [Citation(s) in RCA: 57] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2016] [Revised: 02/10/2017] [Accepted: 03/28/2017] [Indexed: 12/27/2022] Open
Abstract
Multiple myeloma (MM) is a plasma cell malignancy that is still considered to be incurable in most cases. A dominant mutation cluster has been identified in RAS/RAF genes, emphasizing the potential significance of RAS/RAF/MEK/ERK signaling as a therapeutic target. As yet, however, the clinical relevance of this finding is unclear as clinical responses to MEK inhibition in RAS-mutant MM have been mixed. We therefore assessed RAS/RAF mutation status and MEK/ERK pathway activation by both targeted sequencing and phospho-ERK immunohistochemistry in 180 tissue biopsies from 103 patients with newly diagnosed MM (NDMM) and 77 patients with relapsed/refractory MM (rrMM). We found a significant enrichment of RAS/BRAF mutations in rrMM compared to NDMM (P=0.011), which was mainly due to an increase of NRAS mutations (P=0.010). As expected, BRAF mutations were significantly associated with activated downstream signaling. However, only KRAS and not NRAS mutations were associated with pathway activation compared to RAS/BRAFwt (P=0.030). More specifically, only KRASG12D and BRAFV600E were consistently associated with ERK activation (P<0.001 and P=0.006, respectively). Taken together, these results suggest the need for a more specific stratification strategy consisting of both confirmation of protein-level pathway activation as well as detailed RAS/RAF mutation status to allow for a more precise and more effective application of targeted therapies, for example, with BRAF/MEK inhibitors in MM.
Collapse
Affiliation(s)
- J Xu
- Max Eder Group Experimental Therapies for Hematologic Malignancies, Heidelberg University Hospital and German Cancer Research Center (DKFZ), Heidelberg, Germany.,Department of General Pathology, Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.,Department of Internal Medicine V, Heidelberg University Hospital, Heidelberg, Germany
| | - N Pfarr
- Department of General Pathology, Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany
| | - V Endris
- Department of General Pathology, Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany
| | - E K Mai
- Department of Internal Medicine V, Heidelberg University Hospital, Heidelberg, Germany
| | - N H Md Hanafiah
- Max Eder Group Experimental Therapies for Hematologic Malignancies, Heidelberg University Hospital and German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - N Lehners
- Max Eder Group Experimental Therapies for Hematologic Malignancies, Heidelberg University Hospital and German Cancer Research Center (DKFZ), Heidelberg, Germany.,Department of Internal Medicine V, Heidelberg University Hospital, Heidelberg, Germany
| | - R Penzel
- Department of General Pathology, Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany
| | - W Weichert
- Department of General Pathology, Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany
| | - A D Ho
- Department of Internal Medicine V, Heidelberg University Hospital, Heidelberg, Germany
| | - P Schirmacher
- Department of General Pathology, Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany
| | - H Goldschmidt
- Department of Internal Medicine V, Heidelberg University Hospital, Heidelberg, Germany.,National Center for Tumor Diseases (NCT), Heidelberg, Germany
| | - M Andrulis
- Department of General Pathology, Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany
| | - M S Raab
- Max Eder Group Experimental Therapies for Hematologic Malignancies, Heidelberg University Hospital and German Cancer Research Center (DKFZ), Heidelberg, Germany.,Department of Internal Medicine V, Heidelberg University Hospital, Heidelberg, Germany
| |
Collapse
|
|
50
|
Design and synthesis of new RAF kinase-inhibiting antiproliferative quinoline derivatives. Part 2: Diarylurea derivatives. Eur J Med Chem 2017; 127:413-423. [DOI: 10.1016/j.ejmech.2017.01.006] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2016] [Revised: 12/28/2016] [Accepted: 01/04/2017] [Indexed: 01/07/2023]
|