Abstract B033: Resistance to the pan-RAS(ON) tri-complex inhibitor daraxonrasib is overcome by direct multi-KRAS inhibitors, QTX3034 and QTX3544

Abstract Mutant-selective RAS inhibitors have transformed the therapeutic landscape for KRAS-driven cancers, yet the emergence of adaptive and acquired resistance poses challenges to achieving consistent and durable clinical benefit. Acquired resistance to switch II KRAS G12C or G12D inhibitors have been predominantly associated with secondary KRAS mutations and mutational activation of upstream receptor tyrosine kinases. In contrast, KRAS amplifications and mutations of RAS-signaling downstream components are the most frequently reported pan-RAS(ON) tri-complex inhibitor (TCI) resistance mechanisms. Here, we present a detailed preclinical characterization of acquired resistance to the pan-RAS(ON) TCI daraxonrasib across multiple KRAS-mutant cancer cell line models. Our findings identified cyclophilin A (CYPA) loss-of-function (LoF) mutation as a novel resistance mechanism specific to the pan-RAS(ON) TCI. In line with this observation, Quanta’s clinical assets QTX3034 and QTX3544, potently inhibited the proliferation and MAPK signaling of daraxonrasib-resistant cells harboring CYPA mutations, underscoring their potential application as alternative therapeutic options for patients resistant to TCIs. Consistent with previous reports, we also observed CYPA-independent resistance mechanisms in these TCI resistant models such as mutations in the PI3K-AKT-mTORC1 pathway and upregulation of genes involved in the epithelial-mesenchymal (EMT) pathway. Taken together, our study provides new insights into the resistance mechanisms of the pan-RAS(ON) TCI daraxonrasib and suggests that patients refractory to TCI therapeutics may benefit from direct multi-KRAS inhibitors. Citation Format: Jillian M. Silva, Yang J. Zhang, Yang W. Zhang, Elizabeth D. Vo, Arghyotri Sinha, Jennifer Barry, Cameron Pitt, Hong Lin. Resistance to the pan-RAS(ON) tri-complex inhibitor daraxonrasib is overcome by direct multi-KRAS inhibitors, QTX3034 and QTX3544 [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 B033.