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|Ref Type||Journal Article|
|Authors||Ye S, Sharipova D, Kozinova M, Klug LR, D'Souza JW, Belinsky MG, Johnson KJ, Einarson MB, Devarajan K, Zhou Y, Litwin S, Heinrich MC, DeMatteo RP, von Mehren M, Duncan JS, Rink L|
|Title||Identification of Wee1 as target in combination with avapritinib for Gastrointestinal Stromal Tumor treatment.|
|Date||2020 Dec 15|
|Abstract Text||Management of Gastrointestinal stromal tumor (GIST) 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 problem. Development of effective treatment 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 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 (KIT-mutant, PDGFRA-mutant, Succinate dehydrogenase (SDH)-deficient) to identify novel 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 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.|
|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||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|
|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||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|