Abstract IA007: Response and resistance to RAS blockade in solid tumors and beyond

Abstract Anti-RAS therapeutics are transforming the clinical management of RAS-driven cancers and providing unprecedented insight into RAS biology. In this lecture, we discuss key challenges and opportunities emerging from preclinical and clinical studies of mutant-specific and mutant-agnostic RAS inhibitors. Our work focuses on defining mechanisms of response and resistance to RAS blockade, revealing that therapeutic outcomes are shaped by tumor histology and by the specific mutant codon involved. In KRASG12C-mutant non-small cell lung cancer (NSCLC) and colorectal cancer (CRC), responses to KRASG12C inhibitors differ markedly due to distinct levels of receptor tyrosine kinase (RTK) activity. We identified EGFR signaling as the dominant driver of resistance in CRC, findings that directly informed the clinical development and approval of anti-EGFR–based combination therapies for KRASG12C-mutant CRC. Extending beyond tumor lineage, we showed that RAS signaling dependencies are primarily dictated by mutant codon rather than RAS isoform. RASQ61X mutants signal largely independently of upstream RTKs, show sensitivity to MAPK pathway inhibition, and have impaired PI3K/Akt/mTOR signaling. In contrast, RASG12X mutants amplify RTK input to sustain oncogenic signaling through both MAPK and PI3K pathways. Accordingly, combined RAS and RTK inhibition selectively suppresses RASG12X-mutant tumors across cancer types, providing a strong rationale for codon-guided therapeutic strategies. As RAS alterations are present in more than 20% of all human cancers, we are now investigating RAS-mutant hematologic malignancies, where sensitivity to RAS inhibition is influenced by disease stage and epigenetic context. In secondary acute myeloid leukemia (sAML), mutant RAS confer resistance to standard hypomethylating agent–based therapies. We show that azacytidine pretreatment sensitizes RAS-mutant sAML cells to RAS inhibition, inducing synergistic effects on signaling suppression, apoptosis, and tumor control in vitro, in vivo, and in primary patient samples, while sparing normal hematopoietic cells. RAS blockade plays an important role in shaping tumor microenvironment (TME). Preclinical studies indicate that RAS inhibition can alter the immunosuppressive TME and improve outcomes when combined with immune checkpoint inhibitors in preclinical models. To further leverage the immunomodulatory effects, we are evaluating a vaccine-based approach (mKRAS Vax) in combination with immune checkpoint modulators to enhance and prolong responses to RAS inhibition in CRC preclinical models. Together, these findings highlight how tumor context, mutant codon, and epigenetic state shape RAS signaling dependencies. As direct RAS targeting enters routine clinical practice, integrating RAS inhibitors into rational, biology-driven combination strategies will be essential to overcome resistance and extend therapeutic benefit. Our future efforts will focus on exploiting tumor-intrinsic vulnerabilities and microenvironmental interactions to optimize durable responses across RAS-driven malignancies. Citation Format: Sandra Misale. Response and resistance to RAS blockade in solid tumors and beyond [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: RAS Oncogenesis and Therapeutics; 2026 Mar 5-8; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(5_Suppl_1):Abstract nr IA007.