The Therapeutic Landscape for KRAS-Mutated Colorectal Cancers

SIMPLE SUMMARY: More than a third of all colorectal cancers have a KRAS mutation. The complex biology of these cancers has challenged the development of direct targeting inhibitors. Substantial leaps have been made in recent years, with a wave of new generation inhibitors able to specifically target the G12C KRAS mutation. Particularly, Adagrasib and Sotorasib are of note, with several other molecules in development, with the goal of expanding the targets to other KRAS mutations. Therapeutic regimens are being developed to address the emergence of resistance to these inhibitors, including pan-pathway inhibition of adjacent and/or downstream/upstream signaling, blocking metabolic pathways and sensitizing to immunotherapy. The utilization of these other therapies in conjunction with the direct inhibitors provides a significant step forward in the treatment of KRAS mutated colorectal cancers. ABSTRACT: Colorectal cancer is one of the world’s most prevalent and lethal cancers. Mutations of the KRAS gene occur in ~40% of metastatic colorectal cancers. While this cohort has historically been difficult to manage, the last few years have shown exponential growth in the development of selective inhibitors targeting KRAS mutations. Their foremost mechanism of action utilizes the Switch II binding pocket and Cys12 residue of GDP-bound KRAS proteins in G12C mutants, confining them to their inactive state. Sotorasib and Adagrasib, both FDA-approved for the treatment of non-small cell lung cancer (NSCLC), have been pivotal in paving the way for KRAS G12C inhibitors in the clinical setting. Other KRAS inhibitors in development include a multi-targeting KRAS-mutant drug and a G12D mutant drug. Treatment resistance remains an issue with combination treatment regimens including indirect pathway inhibition and immunotherapy providing possible ways to combat this. While KRAS-mutant selective therapy has come a long way, more work is required to make this an effective and viable option for patients with colorectal cancer.