BRAF and MEK Inhibitors in Colorectal Cancer

BRAF mutation has been reported in approximately 10–15% of colorectal cancers. Data also supports presence of BRAF mutations as a poor prognostic factor, as well as a potential biomarker of lack of response to EGFR directed therapy in KRAS wild type colorectal cancer. Like melanoma, BRAF V600E is the most common mutation seen in the RAF family of serine threonine kinases in colorectal cancer, but, unlike melanoma, the response to BRAF inhibitors in this cancer has been limited. Lack of responsiveness in colorectal cancer has been an area of active investigation and studies have postulated EGFR mediated re-activation of MAPK pathway to be a potential mechanism. Since EGFR expression is not as frequent in melanoma, this pathway does not play a significant role in melanoma. Possible strategy to overcome this resistance could be utilization of a combination of agents directed to EGFR and BRAF. Hence a number of ongoing clinical studies are evaluating combination of EGFR targeted agents with BRAF inhibitors.

Another potential approach could be targeting a downstream component of the MAPK pathway. At RPCI, we are evaluating inhibition of ERK, a downstream effector of MAPK pathway, in multiple solid tumors including colorectal cancer. Read about this phase I study.

Additionally, a more effective inhibition of ErbB pathway by combining agents targeting ERBB3 and EGFR may yield superior clinical efficacy and is currently under investigation at RPCI. You can read about this study here.