WCLC 2025 - Posters & ePosters-EP.02.10 Fumarate and Ass1 in KRAS-Mutant NSCLC: The Influence of Cetuximab in Combination With KRAS G12C Inhibitors (Sotorasib and Fulzerasib)

EP.02.10 Fumarate and Ass1 in KRAS-Mutant NSCLC: The Influence of Cetuximab in Combination With KRAS G12C Inhibitors (Sotorasib and Fulzerasib)

Back to course

Pdf Summary

This study from the Fundation Institute of Oncology Rosell investigates the effects of combining cetuximab with KRAS G12C inhibitors—sotorasib and fulzerasib—in KRAS-mutant non-small cell lung cancer (NSCLC) cell lines. Both fulzerasib and sotorasib show broad efficacy across various KRAS G12C mutant cell lines, with synergistic effects demonstrated when used in combination with cetuximab, as indicated by combination index values below 1 in multiple tested lines (H23, MIA PaCa-2, H1792, H358, H2122, H2030). The inhibitors’ potency varies by cell line, with fulzerasib generally showing lower inhibitory concentration (nM) values than sotorasib in some contexts.<br /><br />Genetic profiles varied across the cell lines, with mutations in TP53, STK11, KEAP1, ATM, and other genes, reflecting the complexity of KRAS-mutant NSCLC. The combination treatment effectively mitigated MAPK pathway reactivation, a resistance mechanism often induced by monotherapy with either fulzerasib or sotorasib. This suggests that cetuximab can enhance the durability of KRAS G12C inhibitor responses by preventing downstream signaling rebound.<br /><br />Additionally, treatment with sotorasib or fulzerasib increased fumarate and ASS1 (argininosuccinate synthetase 1) levels in these cells. These metabolic changes may indicate adaptive cellular responses or vulnerabilities that could be exploited for further therapeutic benefit.<br /><br />Overall, the data highlight the potential of combining EGFR-targeting cetuximab with KRAS G12C inhibitors to achieve synergistic anti-tumor activity in KRAS-mutant NSCLC by both enhancing drug efficacy and counteracting adaptive resistance through MAPK pathway modulation and associated metabolic alterations. This strategy merits further clinical investigation for improved management of KRAS G12C-driven lung cancers.

Asset Subtitle

Daniel Olmo González

Meta Tag

Speaker Daniel Olmo González

Topic Tumor Biology – Preclinical Biology

Keywords

KRAS G12C inhibitors

cetuximab

non-small cell lung cancer

sotorasib

fulzerasib

synergistic effects

MAPK pathway reactivation

TP53 mutation

metabolic alterations

EGFR targeting