Abstract 405P
Background
EGFR and aurora kinase (AURKA) elicit adaptive resistance to KRASG12C inhibitors in lung cancer cell lines. Cetuximab suppresses EGFR and AURKA in L858R EGFR mutant cells. Concurrent therapy of cetuximab and MRTX1133 (KRASG12D inhibitor) yields strong synergism in KRASG12D-mutant colorectal cancer. Cetuximab with fulzerasib (KRASG12C inhibitor) attains an 80% response rate in KRASG12C-mutant lung cancer patients. A cetuximab moonlight function in KRAS-mutant colorectal cancer inhibits nuclear factor erythroid-2-related factor 2 (Nrf2).
Methods
The NSCLC KRAS mutant cell lines H358, H23 and H2030 were treated with fulzerasib or sotorasib in combination with cetuximab. Colony formation assays were used to check the inhibitory effect of these treatments. To analyze the mechanism of action of these compounds and its combination western blotting experiments were carried out to analyze the protein expression or activation of the following proteins: NRF2, KEAP1, SLC7A11, AURKA, PSAT1, PRMT1 and PGHDH.
Results
Fulzerasib or sotorasib combined with cetuximab inhibited Nrf2 and SLC7A11 protein expression. Also, AURKA and phosphoserine aminotransferase 1 (PSAT1) were downregulated. In H358 cells cetuximab alone inhibits colony, but not in H23 cells. Concurrent treatment with cetuximab and fulzerasib or sotorasib produced a strong inhibition of colony formation in H358 and H23 cell lines. Fulzerasib had a better inhibitory effect in the formation of colonies than sotorasib and the combination with cetuximab was highly effective in both EGFR H358 and H23 cells.
Conclusions
AURKA and Nrf2 are reported to upregulate serine synthesis enzymes: phosphoglycerate dehydrogenase (PHGDH) and PSAT1. The current study concludes that cetuximab in combination with fulzerasib could exert a moonlight effect by blocking the in blocking Nrf2-SLC7A11, AURKA and serine synthesis pathways. The Nrf2-SLC7A11 and PSAT1 pathways are identified as potential mechanisms of resistance.
Funding
GenFleet Therapeutics (Shanghai) Inc.
Disclosure
All authors have declared no conflicts of interest.