New Research Uncovers How Cancers With Common Mutation Devel
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A new study has given scientists their first look at the genomic landscape of tumors that have grown resistant to drugs targeting the abnormal KRASG12C protein. Their work shows that, far from adopting a common route to becoming resistant, the cells take a strikingly diverse set of avenues, often several at a time.

The findings, underscore the need for new drugs that inhibit KRAS differently than current agents do. And, because resistance can arise through many different mechanisms, effective treatment for these cancers will likely require combinations of KRAS inhibitors and other targeted drugs.

In a multi-institutional effort, researchers collected tumor samples from 38 patients with cancers carrying KRASG12C mutations—27 with NSCLC, 10 with colorectal cancer, and one with cancer of the appendix. Analysis of the samples uncovered possible causes of resistance to adagrasib in 17 of the patients, seven of whom had multiple causes.

The resistance mechanisms fell into three categories:

~ New alterations in KRAS—the development of mutations other than G12C (at amino acid positions such as G12, G13, R68, H95, and Y96) or an increased number of copies of KRASG12C itself.
~ Abnormalities in an array of genes other than KRASG12C. These genes included BRAF, MET, ALK, RET, MAP2K1, and others.
~ Two cases in which lung adenocarcinomas (cancers that start in secretory cells) transitioned to become squamous cell carcinomas, a different subtype of NSCLC.

The number of patients with KRAS alterations and non-KRAS genetic abnormalities was roughly equal, and many patients had both types of resistance mechanisms.

The effort to uncover KRAS mutations associated with drug resistance was led by Andrew Aguirre, MD, Ph.D., of Dana-Farber, Brigham and Women's Hospital and the Broad Institute of MIT and Harvard. The researchers created a series of cell lines that each contained the G12C mutation plus an additional mutation in the KRAS gene. They then ran tests to see which of the doubly mutated genes gave cells the ability to become resistant to sotorasib or an adagrasib-like compound.

They found that some of the new mutations conferred resistance to both agents, whereas others provided resistance to just one. "In addition to identifying resistance mutations that have already occurred in patients receiving adagrasib, our study also provides an atlas of all possible mutations in KRASG12C that can cause resistance to adagrasib and/or sotorasib," Aguirre said.

"These results will be a valuable resource for oncologists to interpret future acquired mutations that occur in patients who become resistant to these drugs and may be used to guide the choice of which KRASG12C inhibitor is right for each patient." The study results point to the variety of ways cancers with KRASG12C mutations can overcome the effects of adagrasib, the authors say.