The majority of gastrointestinal stromal tumors (GIST) harbor constitutively 
activating mutations in KIT tyrosine kinase. Imatinib, sunitinib, and 
regorafenib are available as first-, second-, and third-line targeted therapies, 
respectively, for metastatic or unresectable KIT-driven GIST. Treatment of 
patients with GIST with KIT kinase inhibitors generally leads to a partial 
response or stable disease but most patients eventually progress by developing 
secondary resistance mutations in KIT. Tumor heterogeneity for secondary 
resistant KIT mutations within the same patient adds further complexity to GIST 
treatment. Several other mechanisms converge and reactivate the MAPK pathway 
upon KIT/PDGFRA-targeted inhibition, generating treatment adaptation and 
impairing cytotoxicity. To address the multiple potential pathways of drug 
resistance in GIST, the KIT/PDGFRA inhibitor ripretinib was combined with MEK 
inhibitors in cell lines and mouse models. Ripretinib potently inhibits a broad 
spectrum of primary and drug-resistant KIT/PDGFRA mutants and is approved by the 
FDA for the treatment of adult patients with advanced GIST who have received 
previous treatment with 3 or more kinase inhibitors, including imatinib. Here we 
show that ripretinib treatment in combination with MEK inhibitors is effective 
at inducing and enhancing the apoptotic response and preventing growth of 
resistant colonies in both imatinib-sensitive and -resistant GIST cell lines, 
even after long-term removal of drugs. The effect was also observed in systemic 
mastocytosis (SM) cells, wherein the primary drug-resistant KIT D816V is the 
driver mutation. Our results show that the combination of KIT and MEK inhibition 
has the potential to induce cytocidal responses in GIST and SM cells.