Lu65

Direct Tumor Recognition by and Cytokine Expression Status of PLAC1-Specific CD4 Helper T Cells

KRAS is a frequently mutated oncogene in cancers, including non-small cell lung cancer (NSCLC). While KRAS G12C inhibitors like AMG510 have shown promise in early clinical trials, resistance mechanisms remain unclear. Adachi et al. aimed to identify intrinsic and acquired resistance mechanisms to KRAS G12C inhibitors using a panel of KRAS G12C-mutant lung cancer cell lines.

In addition to a KRAS-dependency signature associated with sensitivity to AMG510, GSEA revealed a significant enrichment of genes related to epithelial-mesenchymal transition (EMT) in AMG510-resistant cell lines (Fig. 1A). Sensitivity to AMG510 was strongly correlated with EMT scoring derived from various cancer-specific transcriptomic EMT signatures (Fig. 1B). To investigate whether EMT contributes to resistance to the KRAS G12C inhibitor AMG510, they induced EMT through chronic TGFβ treatment in the epithelial marker-positive and AMG510-sensitive NCI-H358 and LU65 cells. Remarkably, inducing EMT in these cells was sufficient to confer resistance to AMG510 (Fig. 1C and D). EMT induction led to changes in the expression of several receptor tyrosine kinases (RTKs), such as ERBB3 and FGFR1, and coincided with the suppression of E-cadherin (Fig. 1C). Importantly, EMT induction resulted in reduced expression and activation of KRAS, similar to what was observed in AMG510-insensitive cell lines (Fig. 1E). Notably, despite the suppression of KRAS, ERK phosphorylation was paradoxically higher in EMT-induced cells.