Study: Mutations Make Cancer Resistant to Therapies Targeting KRAS

Researchers at the Massachusetts General Hospital (MGH) have identified the first resistance mechanisms that may occur to drugs that target a mutated form of the KRAS gene and identified strategies to overcome them, according to findings published in Cancer Discovery.

One mutated version of KRAS that commonly arises in cancer cells is called KRAS(G12C) and it produces a mutated KRAS protein that allows the cells to grow and spread in the body.

“Now, with the development of KRAS(G12C) inhibitors, the treatment landscape for KRAS-mutant cancers is rapidly evolving,” said co-lead author Jessica J. Lin, MD, an attending physician in the Center for Thoracic Cancers and the Termeer Center for Targeted Therapies at MGH, in a press release. “KRAS(G12C) inhibitors adagrasib and sotorasib have recently demonstrated promising efficacy and safety in advanced KRAS(G12C)-mutant cancers.”

An analysis by Lin and her team found various new tumor mutations in addition to KRAS(G12C), as many of these mutations ultimately reactivated the signaling pathway driven by KRAS in cells, which is involved in cell growth and division. Additionally, the team found a novel KRAS(Y96D) mutation that further alters the structure of the KRAS(G12C) protein so that it is no longer effectively blocked by adagrasib, sotorasib, or other inhibitors. However, experiments revealed that 1 KRAS(G12C) inhibitor, which binds in a different way to the active state of KRAS, could still overcome this multi-mutant KRAS protein, according to the study.

“Our results suggest a role for the rational design of distinct KRAS inhibitors to overcome resistance to KRAS(G12C) inhibitors in patients,” Lin said in the press release. “Additionally, the convergence of different mutations towards RAS-MAPK reactivation suggests that the greater impact for KRAS(G12C) inhibitors may be in combination with other drugs such as downstream RAS-MAPK pathway inhibitors. These are all areas that need to be further explored.”

Lin emphasized that this study represents only the tip of the iceberg.

“We need to extend our findings and better understand the scope of resistance mechanisms that occur in patients treated with KRAS(G12C) inhibitors and other mutant-specific KRAS inhibitors,” she added in the press release. “Ongoing efforts to comprehensively understand the mechanisms of resistance to mutant-specific KRAS inhibitors will be pivotal in developing novel therapeutic approaches and improving care for patients with KRAS-mutant cancers.”

REFERENCE

Scientists uncover mutations that make cancer resistant to therapies targeting KRAS. Massachusetts General Hospital. Published April 6, 2021. Accessed April 8, 2021. https://www.massgeneral.org/news/press-release/Scientists-uncover-mutations-that-make-cancer-resistant-to-therapies-targeting-KRAS