Liquid biopsy techniques uncover acquired resistance mechanisms to KRAS G12C inhibitors

Agilent Technologies Inc. (NYSE: A) today announced the publication of a study carried out in partnership with Resolution Bioscience (a part of Agilent) and Dana-Farber Cancer Institute. The paper was published in the New England Journal of Medicine (NEJM) on June 24 and is titled "Acquired Resistance to KRAS G12C Inhibition in Cancer." It demonstrates the clinical utility of liquid biopsy techniques to detect resistance to targeted therapies, including inhibitors of KRAS, one of the most commonly mutated oncogenes in cancer.

KRAS G12C inhibitors, such as adagrasib, have shown promising efficacy in clinical trials, however, mechanisms of acquired resistance are not yet fully understood. Leveraging cell-free DNA (cfDNA) analysis, this study was conducted to investigate mutations that arise that may confer resistance to patients treated with KRAS inhibitors, including adagrasib and to better understand the process of acquired resistance and to identify new strategies to combat acquired resistance.

The results of the study showed KRAS G12C cancers have diverse genomic and histologic mechanisms, including point mutations, copy number changes, and fusions, that appear to impart resistance to KRAS G12C inhibitors. Developing therapeutic strategies to delay and overcome drug resistance will be an essential component in improving therapeutic outcomes in cancer patients.

“While results from these early clinical trials are encouraging, the cancer usually becomes resistant to these drugs,” said Dana-Farber’s Mark Awad, MD, Ph.D., the co-first author of the paper with Shengwu Liu, Ph.D., also of Dana-Farber. “The mechanisms of resistance – the genomic and other changes that occur that allow the cancer to begin growing again – are largely unknown. This study sought to identify them.”

“Given the high prevalence of KRAS driven cancers and resulting unmet medical need, elucidating the genetic underpinnings of acquired resistance to KRAS inhibitors at the time of progression is critical,” Mark Li, CEO of Resolution Bioscience, said. "Importantly, in this study, more than three times as many patients were able to be genotyped by cfDNA compared to tissue alone at the time of progression. Furthermore, this study highlights the importance for cfDNA assays to accurately detect all major types of genetic aberrations, including gene fusions and copy number variations.”

Agilent's Resolution Bioscience team has partnered with Mirati Therapeutics Inc. (NASDAQ: MRTX) to use the Resolution ctDx FIRST assay as a companion diagnostic (CDx) in support of adagrasib for identifying patients with non-small cell lung cancer patients that harbor a KRAS G12C mutation. Liquid biopsy biomarker testing of patients in the adagrasib registrational clinical trial is being performed in Resolution’s clinical lab based in Kirkland, Washington.

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