WCLC 2025 - Posters & ePosters-EP.02.12 Identifying Acquired Resistance Mechanisms to Sotorasib in G12C Lung Adenocarcinoma (LuAD) Cell Lines (CL)

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This study investigates mechanisms of acquired resistance to the KRAS p.G12C inhibitor sotorasib in lung adenocarcinoma (LuAD) cell lines, aiming to identify pathways to overcome resistance. KRAS p.G12C mutations are common in LuAD, and sotorasib selectively inhibits mutant KRAS by locking it in an inactive GDP-bound state. Despite initial clinical efficacy, resistance often develops.<br /><br />Researchers developed sotorasib-resistant (SR) models from commercial LuAD cell lines and a patient-derived cell line. They performed whole exome sequencing (WES), RNA sequencing, and assays measuring KRAS activation and downstream signaling. Resistant clones showed varied sensitivity: some retained partial sensitivity, while others demonstrated high resistance with increased IC50 values.<br /><br />Genetic analysis revealed key resistance mechanisms including KRAS gene amplification and a secondary KRAS mutation (p.G12V) in certain resistant models. Transcriptomic profiling indicated increased expression of genes such as MRAS, AXL, and FGFR1 in resistant clones. Functionally, resistant cells either maintained or restored high levels of active RAS-GTP despite sotorasib treatment, unlike sensitive parental lines where active RAS was suppressed.<br /><br />Downstream signaling analysis showed persistent MAPK pathway activity in some resistant clones, alongside activation of the PI3K-AKT-mTOR pathway, suggesting alternative survival routes. Functional drug assays demonstrated that MEK inhibitor trametinib could overcome resistance and that the SHP2 inhibitor TNO155, though ineffective alone, synergized with sotorasib to suppress viability in both intrinsic and acquired resistance models.<br /><br />Overall, acquired resistance to sotorasib involves KRAS amplification, secondary KRAS mutations, and activation of bypass pathways. Combining sotorasib with MEK or SHP2 inhibitors may enhance treatment efficacy and help prevent or overcome resistance in KRAS p.G12C mutant lung adenocarcinoma. This study provides preclinical evidence supporting combination therapeutic strategies for improving outcomes in patients with resistant KRAS-mutant LuAD.

Asset Subtitle

Marc Cucurtull Salamero

Meta Tag

Speaker Marc Cucurtull Salamero

Topic Tumor Biology – Preclinical Biology

Keywords

KRAS p.G12C mutation

sotorasib resistance

lung adenocarcinoma

KRAS gene amplification

secondary KRAS mutations

MAPK pathway activation

PI3K-AKT-mTOR pathway

MEK inhibitor trametinib

SHP2 inhibitor TNO155

combination therapy