New research uncovers how cancers with common mutation develop resistance to specific drugs


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A new study by researchers at the Dana-Farber Cancer Institute 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 pathway to become resistant, cells adopt a set of surprisingly diverse avenues, often diverse at once.

The findings, communicated online today at New England Journal of Medicine, emphasize the need for new drugs that inhibit KRAS differently than current agents do. And, because resistance can arise through many different mechanisms, effective treatment of these cancers will likely require combinations of KRAS inhibitors and other specific drugs.

“Mutations in the KRAS gene are quite common in all types of cancer,” said Mark Awad, MD, Ph.D. of Dana-Farber, co-first author of the article with Shengwu Liu, Ph.D., also of Dana-Farber. . “The particular mutation we focused on in this study, KRASG12C, is found in approximately 13% of non-small cell lung cancers. [NSCLC], where it is often associated with tobacco use, up to 3% of colorectal cancers and less frequently in other cancers. Although no specific therapy has been approved for this specific molecular subtype, two inhibitors of the KRASG12C protein – adagrasib and sotorasib – have been shown to be promising in clinical trials, especially in patients with NSCLC. “

“Although they result from those early years they are encouraging, cancer is usually resistant to these drugs, “Awad continued.” The mechanisms of resistance (genomic and other changes that occur that allow cancer to start growing again) are unknown. This study sought to identify them. “

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

Resistance mechanisms were divided into three categories:

  • New alterations in KRAS: the development of mutations other than G12C (in amino acid positions such as G12, G13, R68, H95 and Y96) or a greater number of copies of the same KRASG12C.
  • Anomalies in a number of genes other than KRASG12C. These genes include BRAF, MET, ALK, RET, MAP2K1 and others.
  • Two cases in which pulmonary adenocarcinomas (cancers that begin in secretory cells) became squamous cell carcinomas, a subtype different from NSCLC.

The number of patients with KRAS disorders and non-KRAS genetic abnormalities was approximately the same, and many patients had both types of resistance mechanisms.

The effort to discover KRAS mutations associated with drug resistance was also led by the study’s lead author, Andrew Aguirre, MD, Ph.D., Dana-Farber, Brigham and Women’s Hospital, and Broad Institute of MIT and Harvard. Aguirre and colleagues created a series of cell lines, each containing the G12C mutation plus an additional mutation elsewhere in the KRAS gene. The set represented all possible second mutations in KRASG12C that would result in an abnormal protein. The researchers then performed tests to see which of the doubly mutated genes gave cells the ability to become resistant to sotorasib or an adagrasib-like compound. They also tested mutated versions of KRASG12C that the team had identified in patients.

They found that some of the new mutations conferred resistance to both agents, while others provided resistance to only 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 may 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 can be used to guide the choice of which KRASG12C inhibitor is appropriate for each patient.”

The results of the study point to the variety of forms of cancer with KRASG12C they can outweigh the effects of adagrasib, the authors say. “Cancers with the KRASG12C mutation make up a large proportion of all lung cancers and many pharmaceutical companies are developing KRASG12C inhibitors,” Awad noted. “The hope is that studies like this, which uncover mechanisms of resistance, will help drive future studies of combination therapies to delay or prevent resistance or overcome it when it occurs.”

The second drug targeted at KRASG12C shows benefits in mutated non-small cell lung cancer

More information:
New England Journal of Medicine (2021).

Citation: New research discovers how cancers with common mutation develop resistance to specific drugs (2021, June 23) recovered on June 23, 2021 at -mutation-resistance.html

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