Combination Therapy May Be Key to Treating KRAS-Mutant NSCLC
Posted: Friday, May 3, 2019
Acknowledging that researchers have suffered “historical disappointments” in the targeted treatment approaches that have been attempted to address the KRAS oncogene in non–small cell lung cancer (NSCLC), a team writing in EBioMedicine (published by The Lancet) nonetheless forecasted that emerging treatment combinations portend “real progress in this subgroup of unmet need.” The review article’s authors predicted that direct inhibitors of KRAS combined with immunotherapy may be the key.
Corresponding author Colin R. Lindsay, MD, of the University of Manchester, United Kingdom, and colleagues discussed other investigators’ previous work showing that KRAS mutation is vulnerable to immunotherapy approaches, such as PD-L1 blockade, in particular when the TP53 co-mutation is present. Yet among the therapies targeted to KRAS mutations that have not fulfilled their initial promise are farnesyl transferase inhibition, downstream MEK inhibition, and synthetic lethality screens.
However, several direct inhibitors of oncogenic KRAS are currently in preclinical development. “The most advanced of these compounds target the G12C subtype typical to NSCLC, preventing nucleotide exchange and maintaining K-Ras in an inactive GDP [guanosine diphosphate]-bound state,” the authors wrote in support of their optimism. In addition, recent characterization “of a direct mechanistic link between oncogenic KRAS and stabilization of PD-L1 mRNA offer[s] a timely reminder that preclinical/clinical research assessing tumor genetics and the tumor microenvironment must be considered in the same space.”
With these new revelations and others leading to more trials, “we anticipate that KRAS-mutant NSCLC will be the most important molecular subset of cancer to evaluate the combination of small molecules and immune checkpoint inhibitors,” Dr. Lindsay and colleagues stated. KRAS, they reminded, is the most frequent oncogene in NSCLC.
Disclosure: The study authors’ disclosure information may be found at ebiomedicine.com.