| Autor: |
Yan Zhou, Katherine J. Johnson, Margret B. Einarson, Lilli Klug, Samuel Litwin, Dinara Sharipova, Shuai Ye, James S. Duncan, Martin G. Belinsky, Michael Heinrich, Lori Rink, Ronald P. DeMatteo, Jimson W. D’Souza, Marya Kozinova, Karthik Devarajan, Margaret von Mehren |
| Rok vydání: |
2020 |
| Předmět: |
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| DOI: |
10.1101/2020.06.07.138693 |
| Popis: |
Management of gastrointestinal stromal tumor (GIST) has been revolutionized by the identification of activating mutations in KIT and PDGFRA, and the clinical application of receptor tyrosine kinase (RTK) inhibitors in the advanced disease setting. 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 the majority of GIST, resistance to these agents remains a significant clinical problem. Development of effective treatment strategies for refractory GIST subtypes requires identification of novel targets to provide additional therapeutic options. Global kinome profiling has the potential to identify critical signaling networks and reveal protein kinases that are essential in GIST. Using Multiplexed Inhibitor Beads and Mass Spectrometry, 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 and identified kinases that are universally activated in all GIST, as well as kinases that are unique to each subtype. Kinome profiling in combination with loss-of-function assays identified a significant role for the G2-M tyrosine kinase, Wee1, in GIST cell survival.In vitroandin vivostudies revealed significant efficacy of MK-1775 (Wee1 inhibitor) in combination with avapritinib inKITandPDGFRA-mutant GIST cell lines, and notable efficacy of MK-1775 as a single agent in thePDGFRA-mutant line. These studies provide strong preclinical justification for the use of MK-1775 in GIST. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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