Genomic Profiling Reveals Multiple Resistance Mechanisms of Cancers Against KRAS Inhibitors

KRAS is a major cancer driver mutated in around 30%-40% of colon cancers and 15%-20% of lung cancers. Developing inhibitors for KRAS is a challenge, and until very recently, KRAS was considered “undruggable.” However, last month, Amgen’s  Lumakras (sotorasib) became the first FDA-approved drug against the G12C-mutant KRAS. On June 24th, another KRAS inhibitor, Mirati Therapeutics’ adagrasib, received the FDA’s Breakthrough Therapy designation.

At this juncture, new clinical trial data, emerging from a multi-institutional collaboration led by Dana-Farber Cancer Institute, has shown that cancer cells develop resistance against KRASG12C inhibitors within a few months of treatment. The study published in The New England Journal of Medicine has uncovered some of the diverse avenues by which cancer cells acquire resistance against adagrasib.

The landmark study used genomic testing to analyze samples from 38 patients that developed resistance to adagrasib. The study used Foundation Medicine’s FoundationOneLiquid CDx, an FDA-approved diagnostic test that uses qualitative next-generation sequencing, to analyze over 300 genes using circulating tumor DNA (ctDNA). The test aims to identify mutations and use that information to match patients with relevant, targeted therapies. For this study, the test was re-proposed to identify changes that could lead to resistance.

Identification of Resistance Mechanisms

Using this and other tests, the scientists identified putative resistance mechanisms in 45% of the patients. These resistance mechanisms fell into three categories:

1. Mutations in KRAS – New mutations emerged either in the pocket where adagrasib binds or in distant sites that further activate KRAS.
2. Activation of alternative pathways – Resistance was acquired by activating other receptor tyrosine kinase-RAS-MAPK family members or rearranging oncogenic genes.
3. Transformation into a different cancer subtype – In two patients, the cancer cells had histologically changed from adenocarcinoma to a squamous-cell carcinoma. Interestingly, using ctDNA, FoundationOneLiquid CDx test identified multiple resistance alterations in 18% of the patients. 

“Resistance mechanisms to cancer treatment is often complex, which is challenging for oncologists and researchers to describe and effectively counter. That’s why we were excited to help incorporate genomic testing through Foundation Medicine’s comprehensive liquid biopsy assay into this study – one of the first analyzing resistance mechanisms to KRAS inhibitors,” said Alexa Schrock, Ph.D., Director, Clinical Development at Foundation Medicine.

Speaking exclusively to GeneOnline, Dr. Schrock said, “Studies that throw light on resistance mechanisms are a step in the right direction. We finally have a KRAS inhibitor in the clinic after several years of learning about the cancer driver. I think these results would advance the field immensely and inform scientists as to what we must be looking for with genomic profiling.”

She noted that a patient’s treatment journey would involve multiple testing scenarios when resistance to cancer therapies emerges. Liquid biopsy assays can provide a unique opportunity to testing routinely. Besides, they help study the dynamic nature of resistance mechanisms and adjust therapy accordingly.

“Comprehensive liquid biopsy assays not only enable widespread access to genomic testing, which is particularly appealing to patients with treatment resistance, but they also provide insights to help drive the development of new therapeutic approaches for these patients,” she added.

Validating the Effects of the Mutations

Additionally, the researchers investigated whether the mutations observed in adagrasib resistant cancers convey resistance to sotorasib. To test this, they modified the KRAS of cells in the lab to introduce mutations identified in patients. Since the drugs have different binding mechanisms, not all mutations that conveyed resistance to adagrasib resulted in resistance against sotorasib.

Going a step further, the team tried to identify all possible mutations in the KRAS protein that could lead to resistance against these inhibitors. They mutated every single amino acid within the KRASG12C backbone allele. Most mutations that conveyed protection for both inhibitors were in or around the binding site, but some mutations far from the binding site also resulted in resistance.

Together these results highlight the need for combination therapies and the development of more KRAS inhibitors.

Editor: Rajaneesh K. Gopinath, Ph.D.

Related Article: We Have a Winner! Amgen Grabs First FDA Nod in the Race for Undruggable KRAS

Author

Daniel Ojeda