Making Progress in Targeting KRAS in Non–Small Cell Lung Cancer
Posted: Thursday, June 3, 2021
Clinical trials featured in an article in Cell Reports Medicines illustrate promising interim results using small-molecule inhibitors for patients with KRAS mutations in non–small cell lung cancer (NSCLC). A research team led by Martin Sattler, PhD, of the Dana-Farber Cancer Institute, and colleagues highlighted complementary approaches to NSCLC that act on immune self-defenses within the context of the KRAS ecosystem.
The KRAS oncogenic driver in lung cancer was previously considered an “undruggable target,” due to the lack of binding pockets for drug interaction with specific small-molecule inhibitors. Though few treatments are available for patients with KRAS-mutant NSCLC, different strategies are under investigation to target KRAS through direct or indirect means. The researchers described four ways to address KRAS-mutant NSCLC: immune checkpoint inhibitors, KRAS neoantigen targeting, direct KRAS inhibitors, and KRAS-signaling inhibitors.
“KRAS inhibitors targeting specific mutations such as AMG 510 and MRTX849 are the most promising therapeutic approaches. However, the biggest challenge that could prevent them from having a lasting impact in the clinic is therapeutic resistance caused by resistance mutations, phenotypic switching, and tumor plasticity, which has been noted in other targeted therapies such as EGFR and ALK,” the authors commented.
The investigations are motivated by a more robust understanding of the mechanisms that drive KRAS mutations, improved KRAS-targeted drugs, and immunologic approaches aimed at yielding immune responses against KRAS neoantigens. In addition, interim results highlighted improbable new targets for lung cancer therapy that may ultimately improve this patient group's survival.
Disclosure: Full authors’ disclosures are available at cell.com.