Co-mutations and KRAS G12C inhibitor efficacy in advanced NSCLC. Cancer discovery Negrao, M. V., Araujo, H. A., Lamberti, G., Cooper, A. J., Akhave, N. S., Zhou, T., Delasos, L., Hicks, J. K., Aldea, M., Minuti, G., Hines, J., Aredo, J. V., Dennis, M. J., Chakrabarti, T., Scott, S. C., Bironzo, P., Scheffler, M., Christopoulos, P., Stenzinger, A., Riess, J. W., Kim, S. Y., Goldberg, S. B., Li, M., Wang, Q., Qing, Y., Ni, Y., Do, M. T., Lee, R., Ricciuti, B., Alessi, J. V., Wang, J., Resuli, B., Landi, L., Tseng, S. C., Nishino, M., Digumarthy, S. R., Rinsurongkawong, W., Rinsurongkawong, V., Vaporciyan, A. A., Blumenschein, G. R., Zhang, J., Owen, D. H., Blakely, C. M., Mountzios, G., Shu, C. A., Bestvina, C. M., Garassino, M. C., Marrone, K. A., Gray, J. E., Patel, S. P., Cummings, A. L., Wakelee, H. A., Wolf, J., Scagliotti, G. V., Cappuzzo, F., Barlesi, F., Patil, P. D., Drusbosky, L., Gibbons, D. L., Meric-Bernstam, F., Lee, J. J., Heymach, J. V., Hong, D. S., Heist, R. S., Awad, M. M., Skoulidis, F. 2023


Molecular modifiers of KRAS G12C inhibitor (KRAS G12Ci) efficacy in advanced KRAS G12C-mutant NSCLC are poorly defined. In a large unbiased clinico-genomic analysis of 424 NSCLC patients, we identified and validated co-alterations in KEAP1, SMARCA4 and CDKN2A as major independent determinants of inferior clinical outcomes with KRAS G12Ci monotherapy. Collectively, co-mutations in these three tumor suppressor genes segregated patients into distinct prognostic subgroups and captured ~50% of those with early disease progression (PFS=3 months) with KRAS G12Ci. Pathway-level integration of less prevalent co-alterations in functionally related genes nominated PI3K/AKT/MTOR pathway and additional baseline RAS gene alterations, including amplifications, as candidate drivers of inferior outcomes with KRAS G12Ci, and revealed a possible association between defective DNA damage response/repair and improved KRAS G12Ci efficacy. Our findings propose a framework for patient stratification and clinical outcome prediction in KRAS G12C-mutant NSCLC that can inform rational selection and appropriate tailoring of emerging combination therapies.

View details for DOI 10.1158/2159-8290.CD-22-1420

View details for PubMedID 37068173