Tumor-selective effects of active RAS inhibition in pancreatic ductal adenocarcinoma

• DOI: 10.1101/2023.12.03.569791
• Publication Date: 2023-12-04T22:50:10Z
• Authors: Urszula N. Wasko; Jingjing Jiang; Alvaro Curiel-Garcia; Yingyun Wang; Bianca Lee; Margo Orlen; Kristina Drizyte-...; Marie Menard; Julien Dilly; Stephen A. Sastra; Carmine F. Palermo; Tanner Dalton; Marie C. Hasselluhn; Amanda R. Decker-...; Stephanie Chang; Lingyan Jiang; Xing Wei; Yu C. Yang; Ciara Helland; Haley Courtney; Yevgeniy Gindin; Ruiping Zhao; Samantha B. Kemp; Cynthia Clendenin; Rina Sor; Will Vostrejs; Amber A. Amparo; Priya S. Hibshman; Matthew G. Rees; Melissa M. Ronan; Jennifer A. Roth; Basil Bakir; Michael A. Badgley; John A. Chabot; Michael D. Kluger; Gulam A. Manji; Elsa Quintana; Zhengping Wang; Jacqueline A. M. ...; Matthew Holderfield; David Wildes; Andrew J. Aguirre; Channing J. Der; Robert H. Vonderh...; Ben Z. Stanger; Mallika Singh; Kenneth P. Olive

Summary Broad-spectrum RAS inhibition holds the potential to benefit roughly a quarter of human cancer patients whose tumors are driven by mutations. However, impact inhibiting functions in normal tissues is not known. RMC-7977 highly selective inhibitor active (GTP-bound) forms KRAS, HRAS, and NRAS, with affinity for both mutant wild type (WT) variants. As >90% pancreatic ductal adenocarcinoma (PDAC) cases activating mutations KRAS , we assessed therapeutic comprehensive range PDAC models, including murine cell lines, patient-derived organoids, explants, subcutaneous orthotopic cell-line or patient derived xenografts, syngeneic allografts, genetically engineered mouse models. We observed broad pronounced anti-tumor activity across these models following direct at doses concentrations that were well-tolerated vivo . Pharmacological analyses revealed divergent responses tumor versus tissues. Treated exhibited waves apoptosis along sustained proliferative arrest whereas underwent only transient decreases proliferation, no evidence apoptosis. Together, data establish strong preclinical rationale use broad-spectrum setting PDAC.