The Mutant KRAS Gene Up-regulates BCL-XL Protein via STAT3 to Confer Apoptosis Resistance That Is Reversed by BIM Protein Induction and BCL-XL Antagonism.

摘要: In colorectal cancers with oncogenic GTPase Kras (KRAS) mutations, inhibition of downstream MEK/ERK signaling has shown limited efficacy, in part because failure to induce a robust apoptotic response. We studied the mechanism apoptosis resistance mutant KRAS cells and sought enhance efficacy KRAS-specific inhibitor, GDC-0623. GDC-0623 was potently up-regulate BIM expression greater extent versus other MEK inhibitors isogenic HCT116 SW620 colon cancer cells. ERK silencing enhanced up-regulation by that due its loss phosphorylation at Ser69, confirmed BIM-EL phosphorylation-defective (S69G) increased protein stability blocked induction. Despite BIK induction, wild-type remained resistant GDC-0623-induced apoptosis, BCL-XL. knockdown doxycycline-inducible shRNA attenuated BCL-XL expression. sensitized GDC-0623-mediated as did BH3 mimetic ABT-263. plus ABT-263 induced synergistic includes release from sequestration Furthermore, activated p-STAT3 (Tyr705) absence IL-6 secretion, STAT3 reduced mRNA These data suggest contributes KRAS-mediated resistance. Such can be overcome potent induction concurrent antagonism enable