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Gregory J. Riely, MD, PhD
Gregory J. Riely, MD, PhD
Posted: Monday, April 21, 2025
According to Renato Jose da Silva-Oliveira, PhD, of Barretos Cancer Hospital, São Paulo, and colleagues, resistance to the KRAS G12C inhibitor sotorasib appears to trigger epithelial-mesenchymal transition and activate AKT and p38–mediated signaling. Their findings, which were published in the journal Frontiers in Molecular Biosciences, may inform the design of clinical trials and therapeutic strategies to overcome this resistance in patients with non–small cell lung cancer (NSCLC).
“We conceptualized combination therapies that can enhance the therapeutic efficacy of KRAS G12C drugs and restore sensitivity in NSCLC cell lines with sotorasib-acquired resistance,” the investigators commented. “[Our] findings…demonstrate synergic combination with AKT and p38 inhibitors.”
The investigators exposed KRAS G12C–mutant H358 cells to incremental doses of sotorasib (2–512 nM). Resistant clones were subsequently separated by single-cell sorting. Proliferation was assessed in real time using an impedance-based system; protein profiles were quantified by protein arrays; and mRNA expression was evaluated using a comprehensive cancer pathways panel. The investigators used a database comprising patient-derived xenograft models and sotorasib-resistant cell lines to conduct in silico analyses. A web application analyzed the synergistic effect of combining AKT, p38, and EGFR inhibitors. Silencing was performed using endoribonuclease-prepared small-interfering RNA.
The sotorasib-resistant cell line was found to display markers of the mesenchymal-epithelial transition and loss of cell adhesion. The investigators identified 30 overexpressed genes in the resistance model, which seemed to be involved in signaling pathways that activate AKT and increase the expression levels of phosphorylated AKT and p38 proteins. Combination treatment with the AKT inhibitor MK2206 plus the p38 inhibitor adezmapimod, as well as the silencing of AKT expression, appeared to restore sensitivity to sotorasib in resistant cell lines.
Disclosure: The study authors reported no conflicts of interest.
Frontiers in Molecular Biosciences
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