Figure 6.

KEAP1 and STK11 co-mutations regulate resistance to G12Ci + SOS1i.

A-C, Heat map of cell viability and excess over Bliss for the indicated cells treated with a 9×9 matrix of G12Ci ± SOS1i (A), G12Ci dose response curves (B), G12Ci EC₅₀ values (C), and sum of excess over Bliss values for (D).NT (black closed squares), STK11^KO (dk.grey closed circles), KEAP1^KO (grey open squares), and STK11/KEAP1 DKO (lt.grey open circles) H358 cells.* p < 0.05, p < 0.01 vs. NT. Data are the mean from three independent experiments, each experiment had three technical replicates. E, TIC frequency in the indicated cells ± SOS1i. ** χ² > 0.01, *** χ² < 0.001 for SOS1i treated vs. untreated; ### χ² < 0.001 vs. NT. F-G, In situ resistance assays assessing acquired adagrasib (F) or sotorasib (G) resistance in NT (black), STK11^KO (dk.grey), KEAP1^KO (grey), and STK11/KEAP1 DKO (lt.grey) cells. *** p < 0.001 vs. NT. H-I. Assessment of acquired resistance to the G12Ci adagrasib (H) or sotorasib (I) resistance in NT (black), STK11^KO (dark grey), KEAP1^KO (grey), and STK11/KEAP1 DKO (light grey) alone or in the presence of SOS1i (red). *** p < 0.001 for G12Ci vs G12Ci+SOS1i.

J-K. Waterfall plot of percent change in tumor volume from H2030 xenografts left untreated or treated with G12Ci +/− SOS1i for 7d (J) or 10d (K).