Prolonged MEK inhibition leads to acquired resistance and increased invasiveness in KRAS mutant gastric cancer

摘要: Gastric cancer (GC) is one of the most common causes cancer-associated death. However, traditional therapeutic strategies have failed to significantly improve survival patient with advanced GC. While KRAS mutations been found in some patients gastric cancer, an effective therapy treat KRAS-driven has not established yet. To provide a rationale for clinical application kinase inhibitors targeting RAS pathways, we first determined sensitivity GC cell lines harboring or amplification pathway inhibitors. We that MAPK (MEKi and ERKi) were more than AKT inhibitor, suggesting cells are dependent on survival. Further, mutant line acquired resistance MEK order mimic situation inhibitor resistance. A comprehensive analysis tyrosine phosphorylation receptor kinases combination small molecule chemical library screening revealed upregulated c-MET this elevated TKI (crizotinib) PI3K/mTOR dual (BEZ235). also showed migration invasion resistant promoted, crizotinib BEZ235 could inhibit malignant phenotype. Overall, our results indicate prolonged inhibition result which associated increased phenotype pharmacological overcome problem.