There are currently no approved targeted therapies for advanced KRAS mutant (KRASMT) colorectal cancer (CRC). Using a unique systems biology approach, we identified JAK1/2-dependent activation of STAT3 as the key mediator of resistance toMEK inhibitors in KRASMT CRC invitro and invivo.Further analyses identified acute increases in c-MET activity following treatment with MEK inhibitors in KRASMT CRC models, which was demonstrated to promote JAK1/2-STAT3-mediated resistance. Furthermore, activation of c-MET following MEK inhibition was found tobe due to inhibition of the ERK-dependent metalloprotease ADAM17, which normally inhibits c-MET signaling by promoting shedding of its endogenous antagonist, soluble "decoy" MET. Most importantly, pharmacological blockade of this resistance pathway with either c-MET or JAK1/2 inhibitors synergisticallyincreased MEK-inhibitor-induced apoptosis and growth inhibition invitro and invivo in KRASMT models, providing clear rationales for the clinical assessment of these combinations in KRASMT CRC patients.
All Science Journal Classification (ASJC) codes
- Biochemistry, Genetics and Molecular Biology(all)