Activated MKK3/MYC crosstalk impairs dabrafenib response in BRAFV600E colorectal cancer leading to resistance

Abstract

Colorectal cancer (CRC) patients with BRAF mutations develop resistance to BRAF inhibitors at very early stage. Understanding the mechanisms involved in resistance to BRAF inhibitors is required to develop novel therapeutic opportunities for this subtype of CRC patients. CRC cells bearing BRAF mutations are mostly sensitive to the abrogation of MKK3, a specific activator of p38MAPKs signaling, suggesting that BRAF alterations might addict CRC cells to the MKK3/p38MAPK signaling. Interestingly, publicly available gene profiling data show significantly higher MKK3 transcript levels in CRC lines with acquired resistance to BRAF inhibitors. Herein, we investigated the MKK3 roles in the response to BRAF targeting (dabrafenib) with COLO205 and HT29 BRAFV600E CRC lines and derived dabrafenib-resistant (DABR) sublines. We found that in parental cells, but not in DABR cells, dabrafenib reduces MKK3 phosphorylation and induces autophagy and cell death. The MKK3 knock-down induces cell death in DABR cells, whereas MKK3 ectopic expression in parental cells reduces dabrafenib sensitivity. Molecularly, activated MKK3 interacts and co-localizes with MYC, sustaining MYC protein stability and thus preventing the dabrafenib induced effects in CRC DABR cells both in vitro and in vivo. Overall, we identify a novel molecular mechanism beyond the dabrafenib resistance, shedding lights on an uncovered vulnerability for the development of novel therapeutic opportunities in BRAFV600E CRC.