Kinome Profiling of Gastrointestinal Stromal Tumors Using Multiplexed Inhibitor Beads and Mass Spectrometry Identifies Wee1 as Candidate Therapeutic Target
Kinome Profiling of Gastrointestinal Stromal Tumors Using Multiplexed Inhibitor Beads and Mass Spectrometry Identifies Wee1 as Candidate Therapeutic Target
Abstract Gastrointestinal stromal tumor (GIST) management has been revolutionized by the identification of activating mutations in KIT and PDGFRA and clinical application of receptor tyrosine kinase (RTK) inhibitors in advanced disease. Stratification of GIST into molecularly defined subsets provides insight into clinical behavior and response to approved targeted therapies. Although these RTK inhibitors are effective in most GIST, resistance remains a significant clinical obstacle. Development of effective strategies for refractory GIST requires identification of novel targets to provide additional therapeutic options. Global kinome profiling has potential to identify critical signaling networks and reveal protein kinases that are essential in GIST. Using Multiplexed Inhibitor Beads and Mass Spectrometry paired with a super-SILAC kinome standard, we explored the majority of the kinome in GIST specimens from the three most common molecular subtypes to identify novel kinase targets. Kinome profiling revealed distinct signatures in GIST subtypes. PDGFRA-mutant GIST had elevated tumor associated macrophage (TAM) kinases and immunohistochemical analysis confirmed increased TAMs present in these tumors. Kinome profiling with loss-of-function assays revealed a significant role for G2-M tyrosine kinase, Wee1, in GIST survival. In vitro and in vivo studies revealed significant efficacy of MK-1775 (Wee1 inhibitor) in combination with avapritinib in KIT and PDGFRA-mutant GIST cell lines, and notable efficacy of MK-1775 as a monotherapy in the PDGFRA-mutant line. These studies provide strong preclinical justification for the use of MK-1775 in GIST.
D?ˉSouza Jimson、Kozinova Marya、Zhou Yan、Heinrich Michael C.、Sharipova Dinara、Duncan James、DeMatteo Ronald、Rink Lori、Litwin Samuel、Einarson Margret B.、Johnson Katherine J.、Klug Lilli、Devarajan Karthik、von Mehren Margaret、Ye Shuai、Cai Kathy、Belinsky Martin G.
Molecular Therapeutics Program, Fox Chase Cancer CenterMolecular Therapeutics Program, Fox Chase Cancer Center||Pirogov Russian National Research Medical UniversityDepartment of Biostatistics and Bioinformatics, Fox Chase Cancer CenterPortland VA Health Care System and OHSU Knight Cancer InstituteMolecular Therapeutics Program, Fox Chase Cancer CenterCancer Biology Program, Fox Chase Cancer CenterDepartment of Surgery, Perelman School of Medicine, University of PennsylvaniaMolecular Therapeutics Program, Fox Chase Cancer CenterDepartment of Biostatistics and Bioinformatics, Fox Chase Cancer CenterMolecular Therapeutics Program, Fox Chase Cancer CenterCancer Biology Program, Fox Chase Cancer CenterPortland VA Health Care System and OHSU Knight Cancer InstituteDepartment of Biostatistics and Bioinformatics, Fox Chase Cancer CenterMolecular Therapeutics Program, Fox Chase Cancer CenterMolecular Therapeutics Program, Fox Chase Cancer CenterCancer Biology Program, Fox Chase Cancer CenterMolecular Therapeutics Program, Fox Chase Cancer Center
肿瘤学医学研究方法基础医学
D?ˉSouza Jimson,Kozinova Marya,Zhou Yan,Heinrich Michael C.,Sharipova Dinara,Duncan James,DeMatteo Ronald,Rink Lori,Litwin Samuel,Einarson Margret B.,Johnson Katherine J.,Klug Lilli,Devarajan Karthik,von Mehren Margaret,Ye Shuai,Cai Kathy,Belinsky Martin G..Kinome Profiling of Gastrointestinal Stromal Tumors Using Multiplexed Inhibitor Beads and Mass Spectrometry Identifies Wee1 as Candidate Therapeutic Target[EB/OL].(2025-03-28)[2025-05-15].https://www.biorxiv.org/content/10.1101/2020.06.07.138693.点此复制
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