Abstract A026: Senescence driven by pharmacological RAS inhibition potentiates anti-tumor activity of combination therapies in pancreatic cancer

Abstract

Abstract Senescence is a form of stable proliferative arrest that occurs in response to various forms of cellular stress. In established cancer, these include unresolved DNA damage triggered by chemotherapeutic agents or irradiation, re-establishment of tumor suppressive programs, and by drugs that target cell cycle progression. Senescent cells take on a “Senescence Associated Secretory Phenotype” or SASP, characterized by increased expression of proinflammatory cytokines and other factors that modulate the tissue environment. The SASP triggers immune cell infiltration and, in the context of cancer, potent antitumor immunity. This implicates the use of senescence-inducing agents clinically and suggests that senescence biology may be harnessed to increase the fraction of patients that respond to immunotherapy. RAS is mutated in over 90% of pancreatic cancers, but until recently, has been considered to be “undruggable” due to its small size and lack of drug binding pockets. Recent advances in chemical biology have led to the development of several mutant isoform-specific and broad-spectrum RAS-GTP inhibitors, which hold great clinical promise. We have found that, in mouse models of pancreatic cancer, the non-covalent broad-spectrum inhibitor RM-042 and the covalent KRASG12D specific inhibitor RM-044 trigger a senescence-like phenotype characterized by cell cycle arrest and increased SASP expression. RAS inhibitor-mediated senescence enhances the immune surveillance of tumor cells, and this effect is potentiated by certain combination agents. Our results suggest that senescence contributes to RAS inhibitor efficacy in PDAC and reveal strategies to harness the immune system to improve therapy outcomes and circumvent resistance. Citation Format: Caroline Broderick, Riccardo Mezzadra, Alejando Jiminez-Sanchez, Almudena Chaves-Perez, Janelle Simon, Yu-Jui Ho, Exequiel Sisso, Sha Tian, Amanda Kulick, Elisa DeStanchina, Scott W. Lowe. Senescence driven by pharmacological RAS inhibition potentiates anti-tumor activity of combination therapies in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr A026.