Somatic Missense Mutations Identified as Promising Targets of Future Treatment for NSCLC

A first-of-its-kind study analyzing a selected pool of oncogenes has compiled a list of deleterious somatic missense non-synonymous single nucleotide polymorphisms (nsSNPs) as promising targets for future research into drug design and treatments for patients with non-small cell lung cancer (NSCLC).

“Medical practitioners are moving away from conventional histology-driven empirical treatments, platinum-based chemotherapy, and other invasive surgical resections and have started adopting alternate therapies in which therapeutic targets are patient's molecular oncogenic drivers,” explained Ramgopal Dhakar, PhD, Genome and Computational Biology Lab, Department of Biotechnology, Mohanlal Sukhadia, University, Rajasthan, India, and colleagues. The current study hopes to improve the understanding of the pathobiology of lung cancer in order to better decision-making on clinical and therapeutic considerations.

The study utilized a 4-step procedure, beginning with accessing samples (n = 2059) from cBioPortal’s online somatic mutation data for analysis and identifying the oncogenic potential of 661 missense nsSNPs in 16 genes most significantly mutated in NSCLC patients: EGFR, NRAS, KRAS, HER2 (ERBB2), RET, MET, ROS1, FGFR1, BRAF, AKT1, MEK1 (MAP2K1], PIK3CA, PTEN, DDR2, LKB1 (STK11) and ALK.

The study’s second step identified a set of high-confidence nsSNPs (n = 65) based on sequence and structural homology-based prediction. Steps 3 and 4 involved scoring the conservation of amino acid at SNP sites and identifying molecular mechanisms for possible structural and functional effects caused by nsSNPs. These processes further narrowed the total set of nsSNPs down to 29 conserved high-confidence nsSNPs. Of these, 4 were determined to be putative novel rare genetic markers for NSCLC: EGFR N1094Y, BRAF M620I, DDR2 R307L, ALK P1350T.

“From the current study, the NRAS Q61L, ROS A1750D, PTEN M35I, DDR2 R307L, ALK P1112Q, and ALK P1350T have come out to be novel missense nsSNPs that have never been implicated in cancer, and hence, represent novel targets for drug resistance studies as well for early cancer patient's genotyping/screening,” wrote Dr Dhakar et al, concluding, “the list of deleterious non-synonymous somatic mutations in a selected pool of 16 oncogenes can also be considered a promising target for future drug design and therapy for patients with lung adenocarcinomas and squamous cell carcinomas.”

Source:

Dhakar R, Dakal TC, Sharma A. Genetic determinants of lung cancer: Understanding the oncogenic potential of somatic missense mutations. Genomics. 2022;114(4):110401. doi:10.1016/j.ygeno.2022.110401