Mechanisms of Resistance to KRAS Inhibitors

The approval of sotorasib earlier this year was felt to be a watershed moment in cancer therapeutics, primarily because KRAS was considered an “undruggable” target for many years. RAS proteins are a family of prototypical oncogenes that are mutated in many human cancers. KRAS is the most frequently mutated isoform of RAS mutations (86%), and is mutated in 90% of pancreatic, 40% of colorectal, and 30% of lung cancers. Mutant KRAS has long been referred to as an undruggable target because of its unusual shape. Compared with other proteins, its relatively smooth protein structure meant that designing inhibitors to bind to surface grooves was difficult, stalling progress in drug development for many years. The FDA's accelerated approval of the KRAS inhibitor sotorasib was based on a phase 2 trial of 124 previously treated patients with KRAS G12C-mutated non–small cell lung cancer that demonstrated a response rate of 37%, median duration of response of 11 months, and progression-free survival of 6.8 months (NEJM JW Oncol Hem Sep 2021 and N Engl J Med 2021; 384:2371).

Because resistance to targeted therapies inevitably develops, researchers sought to further understand mechanisms of resistance to KRAS GTPase inhibitors. They evaluated matched pre- and post-treatment specimens from 43 patients treated with sotorasib. In 27 of the 43 patients who developed resistance, multiple treatment-emergent alterations occurred in both KRAS and other genes, including NRAS, BRAF, EGFR, and MYC. The researchers found similar treatment-emergent mutations in xenograft models.