MRTX1133 specifically targets oncogenic KRASG12D human and mouse PDAC models and leads to the upregulation of ERBB activation. A, Dose–response analysis of PDOs harboring the KRASWT, KRASG12V, or KRASG12D alleles 5 days after treatment with MRTX1133. B, Immunoblot analyses of the upstream and downstream targets of KRAS signaling in hT102 (KRASWT) and hM1F (KRASG12D) at 0, 3, 24, and 72 hours using 60 nmol/L MRTX1133. C, Quantification of B. D, Dose–response analysis of PDAC cell lines harboring the KRASWT or KRASG12D alleles 3 days after treatment with MRTX1133. E, Immunoblot analyses of the upstream and downstream targets of KRAS in BXPC3 (KRASWT) and SUIT2 (KRASG12D) at 0, 3, 24, and 72 hours using 60 nmol/L MRTX1133 for BXPC3 and SUIT2. F, Quantification of E. G, Dose–response analysis of mouse KRASG12D KPC organoids 3 days after treatment with MRTX1133. H, Immunoblot analyses of the upstream and downstream targets of KRAS in two different KPC mouse organoids (mT3 and mT9) at 0, 3, 24, and 72 hours using 60 nmol/L MRTX1133. I, Quantification of H. J, Dose–response analysis of mouse KRASG12D KPC cell lines 3 days after treatment with MRTX1133. K, Immunoblot analyses of the upstream and downstream targets of KRAS in two different KPC lines at 0, 3, 24, and 72, hours using 60 nmol/L MRTX1133. L, Quantification of K. Data, mean values ± SD. Immunoblots are representative of at least three independent experiments.