Resistance mutation mechanism of KRAS G12C inhibitor

KRAS gene mutations are very common in cancer.

Among the many KRAS G12C targeted drugs, the NSCLC indication for Amgen sotorasib (AMG 510) was approved by the FDA in May this year, and another KRAS G12C inhibitor, adagrasib (MRTX849), also performed very well in clinical trials.

Although the KRAS G12C mutation can be cured, patients and doctors have to face another problem in actual treatment: cancer cells will become resistant

On June 24, in a study on the mechanism of KRAS G12C acquired drug resistance published in the New England Journal of Medicine, researchers at the Dana-Farber Cancer Institute revealed multiple mechanisms by which cancer cells develop drug resistance

Researchers performed histological and genomic analysis on 38 patients with KRAS G12C mutation who had disease progression when receiving adagrasib monotherapy in the KRYSTAL-1 trial, including 27 NSCLC, 10 colorectal cancer, and 1 appendix cancer patient

After analyzing the samples, the researchers identified the possible mechanism of resistance to adagrasib in 17 patients (45%)

Specific resistance mechanisms can be divided into three categories:

Secondary mutation or amplification of KRAS

It activates the RTK-RAS signaling pathway but does not directly change the alternative carcinogenic changes of KRAS itself

The histological transformation of lung adenocarcinoma to squamous cell carcinoma (a subtype of NSCLC) suggests that there may be a non-genetic mechanism of KRAS G12C inhibition

Of the 17 patients whose possible mechanisms of resistance were identified, 14 (82%) had at least one mechanism that was not related to the KRAS gene itself

The researchers also constructed a series of cell lines, each of which contains G12C mutations and other mutations in the KRAS gene

The researchers also conducted in-depth mutation scanning screening for the secondary mutations of KRAS G12C, and the system defined all the mutation maps in KRAS G12C that may cause resistance to adagrasib and sotorasib

"In the future, cancer experts can use these resources to explain the acquired resistance mutations in adagrasib and sotorasib resistant patients, and the mutation map can also be used to guide doctors in choosing the appropriate KRAS G12C inhibitor for patients

In general, the diversity of KRAS mutations in the treatment of KRAS G12C inhibitors may bring new challenges to the development of the next generation of more effective KRAS G12C inhibitors.

In addition, since drug resistance can be produced through many different mechanisms, in order to achieve effective treatment of KRAS G12C mutant cancers and to deal with the drug resistance mechanisms that appear during the treatment of adagrasib or sotorasib, it is necessary to develop an effective combination treatment plan

Reference materials:

[1] Mark MA, Sheng WL, Igor IR, et al.

[2] Nassar AH, Adib E, Kwiatkowski DJ.
Distribution of KRAS G12C somatic mutations across race, sex, and cancer type.
N Engl J Med 2021

[3] New research uncovers how cancers with common gene mutation develop resistance to targeted drugs (Source: Dana-Farber Cancer Institute)