Pan-ERBB inhibitors synergize with KRAS inhibitors in rectal cancer

Background: Emerging RAS inhibitors show promise in treating KRAS-mutated malignancies, but resistance mechanisms limit their clinical efficacy. Given recent clinical findings associating KRAS mutations with reduced response to neoadjuvant therapy in rectal cancer (RC), we aimed to investigate their impact on treatment outcomes and explore potential therapeutic strategies. Methods: We conducted a retrospective analysis of 390 RC patients to evaluate the association of KRAS mutations with disease-free survival (DFS) and response to therapy. We assessed the efficacy of KRAS inhibitors in RC cell lines, patient-derived organoids (PDOs), and patient-derived cell lines (PDCLs), and explored adaptive resistance mechanisms through transcriptomic profiling and unbiased drug screening experiments. Results: Mutant KRAS was associated with a reduced DFS and RCs harboring G12C and G12V mutations had less complete pathological responses. KRAS-mutated RC cells demonstrated adaptive resistance to KRAS inhibitors, characterized by transcriptomic restoration of oncogenic pathways, including MYC and E2F and upregulation of ERBB2/3 gene expression. Consistently, drug screening identified EGFR family inhibitors as potent combinatorial partners, effectively overcoming KRAS inhibitor tolerance by inducing apoptosis. In patient-derived models, the novel pan-RAS inhibitor RMC-6236 combined with EGFR inhibitors demonstrated significant synergistic effects and prevented long-term tumor outgrowth. Conclusion: Our findings highlight the negative impact of KRAS mutations, particularly G12C and G12V, on RC treatment outcomes. Adaptive resistance by transcriptomic upregulation of ERBB genes limits the efficacy of KRAS inhibitors. Combining these with pan-ERBB inhibitors enhances anti-tumor effects in patient-derived cellular RC models showing its potential as alternative to the combination with anti-EGFR antibodies.