Optimal MAPK Inhibition as a Key Component of Therapeutic Strategies for KRAS Mutant Cancers

Ryan B. Corcoran, MD, PhD
KRAS is the most commonly mutated oncogene in human cancer, yet no effective therapeutic strategies currently exist for KRAS mutant cancers. Since KRAS has proven difficult to target directly with small molecules, an alternative approach has focused on inhibiting key downstream effector pathways. Promising therapeutic combination strategies are currently in clinical trials and will be reviewed. Since the MAPK pathway is one of the most important downstream effector pathways of KRAS, MEK inhibitors, which inhibit MAPK signaling, have become common components of targeted therapy combination strategies. However, we find that while MEK inhibitors lead to effective short-term inhibition of MAPK signaling, complex adaptive feedback mechanisms drive MAPK pathway reactivation, reducing the therapeutic efficacy of MEK inhibitors. This vulnerability may be a key factor underlying the recent lack of success of many MEK inhibitor-based combinations in KRAS mutant cancer trials. However, other classes of MAPK inhibitors, such as ERK inhibitors, are less susceptible to adaptive feedback reactivation and can produce more sustained MAPK inhibition and improved efficacy in KRAS mutant cancer cells. Exploration of ERK inhibitors or other approaches to achieve more optimal MAPK inhibition may be key to the development of future targeted therapy combination approaches for KRAS mutant cancers.