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Ref Type Journal Article
PMID (33320833)
Authors Ye S, Sharipova D, Kozinova M, Klug L, D'Souza J, Belinsky MG, Johnson KJ, Einarson MB, Devarajan K, Zhou Y, Litwin S, Heinrich MC, DeMatteo R, von Mehren M, Duncan JS, Rink L
Title Identification of Wee1 as a target in combination with avapritinib for gastrointestinal stromal tumor treatment.
Journal Vol Issue Date Pages Journal Short Title
JCI insight 6 2 2021 Jan 25 JCI Insight
URL
Abstract Text Management of gastrointestinal stromal tumors (GISTs) has been revolutionized by the identification of activating mutations in KIT and PDGFRA and clinical application of RTK inhibitors in advanced disease. Stratification of GISTs into molecularly defined subsets provides insight into clinical behavior and response to approved targeted therapies. Although these RTK inhibitors are effective in most GISTs, resistance remains a significant clinical problem. Development of effective treatment strategies for refractory GISTs 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 essential in GISTs. Using multiplexed inhibitor beads and mass spectrometry, we explored the majority of the kinome in GIST specimens from the 3 most common molecular subtypes (KIT mutant, PDGFRA mutant, and succinate dehydrogenase deficient) to identify kinase targets. Kinome profiling with loss-of-function assays identified an important role for G2/M tyrosine kinase, Wee1, in GIST cell survival. In vitro and in vivo studies revealed significant efficacy of MK-1775 (Wee1 inhibitor) in combination with avapritinib in KIT mutant and PDGFRA mutant GIST cell lines as well as notable efficacy of MK-1775 as a monotherapy in the engineered PDGFRA mutant line. These studies provide strong preclinical justification for the use of MK-1775 in GIST.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
KIT exon 11 del gastrointestinal stromal tumor sensitive Adavosertib + Avapritinib Preclinical - Cell line xenograft Actionable In a preclinical study, the combination of Adavosertib (MK-1775) and Ayvakit (avapritinib) demonstrated an additive effect on inhibiting cell growth and inducing apoptosis in gastrointestinal stromal tumor cells harboring a KIT exon 11 deletion in culture, and inhibited tumor growth and led to prolonged survival in cell line xenograft models (PMID: 33320833). 33320833
KIT exon13 gastrointestinal stromal tumor sensitive Adavosertib + Avapritinib Preclinical - Cell culture Actionable In a preclinical study, the combination of Adavosertib (MK-1775) and Ayvakit (avapritinib) synergized to inhibit growth of a gastrointestinal stromal tumor cell line harboring a KIT exon 13 mutation in culture (PMID: 33320833). 33320833
KIT exon 11 del gastrointestinal stromal tumor no benefit Adavosertib Preclinical - Cell line xenograft Actionable In a preclinical study, Adavosertib (MK-1775) treatment resulted in reduced cell viability of gastrointestinal stromal tumor cells harboring a KIT exon 11 deletion in culture, but did not lead to improved tumor growth inhibition or prolonged survival compared to controls in cell line xenograft models (PMID: 33320833). 33320833
KIT exon 11 del gastrointestinal stromal tumor sensitive Avapritinib Preclinical - Cell line xenograft Actionable In a preclinical study, Ayvakit (avapritinib) inhibited cell growth and induced cell cycle arrest in gastrointestinal stromal tumor cells harboring a KIT exon 11 deletion in culture, and inhibited tumor growth and led to prolonged survival in cell line xenograft models (PMID: 33320833). 33320833