Resistance to current lines of therap. in gastrointestinal stromal tumors (GIST) can occur through a variety of secondary mutations that occur in KIT. Novel therapeutics are still needed to address the mutational heterogeneity of KIT in GIST patients. In this study, Gupta and collaborators demonstrate the broad spectrum of ripretinib against primary and secondary drug-resistant mutations. Ripretinib is a “switch-control” kinase inhibitor designed to address even aggressively activated mutants to generate inactive conformations. Knowing that imatinib and MEK inhibition previously showed promise against imatinib-sensitive tumors, the authors also demonstrate the potency of combining ripretinib with MEKi in vitro and in vivo.

KRAS mutations are present in up to 95% of pancreatic ductal adenocarcinoma (PDAC) cases. Inhibiting MEK (downstream of KRAS) would therefore appear to be a viable strategy for treating PDAC. Unfortunately, MEK inhibition as a monotherapy has been suboptimal in preclinical and clinical studies. Since CDKN2A mutations are...

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