Irreversible Pan-ERBB inhibitors work synergistically with MRTX1133 in vitro. A, Evaluation of the synergistic effect of MRTX1133 with afatinib (panERBB inhibitor), lapatinib (EGFR/HER2 inhibitor), erlotinib (EGFR inhibitor), trametinib (MEK1/2 inhibitor), and ulixertinib (ERK1/2 inhibitor) using the BLISS synergy model in hF44 PDO, B and C, SUIT2 (B), and ASPC1 (C) show the potent and consistent synergy of MRTX1133 with afatinib. D–F, Western blot analyses of the upstream and downstream pathway targets of KRAS show a synergistic downregulation of the expression of EGFR and HER2 in hM1F (D), SUIT2 (E), and ASPC1 (F). G–I, Quantification of D, E, and F, respectively. Data, mean values ± SD. Immunoblots are representative of at least three independent experiments.