Abstract 3961: Cancer stem cells, not bulk tumor cells, predict mechanisms of resistance to SMO inhibitors in SHH medulloblastoma

Abstract The emergence of primary and acquired treatment resistance significantly reduces the clinical utility of many effective targeted therapies. Both genetic and epigenetic mechanisms of drug resistance have been reported in literature; however, whether these mechanisms are stochastically selected in individual tumors or governed by a predictable underlying principle is unknown.Here, we report that one can predict a priori the resistance mechanism that will arise in individual SMO inhibitor (SMOi)-resistant SHH medulloblastoma (MB), based on different CSC phenotypes in each tumor. We show that the dependence of cancer stem cells (CSCs), not bulk tumor cells, on the targeted pathway (sonic hedgehog (SHH) pathway) determines the molecular mechanism of resistance in individual tumors. Using both spontaneous (Fsmo;GFAP-cre) and transplantable (Ptch+/-;p53) mouse models of SHH MB treated with a Smoothened inhibitor, sonidegib/LDE225, we show that genetic-based resistance occurs only when the CSCs depend on the targeted pathway. In contrast, SHH MBs containing SHH-dependent bulk tumor cells but SHH-independent CSCs (SI-CSCs), acquire resistance through epigenetic reprogramming. Mechanistically, we discovered that the elevated proteasome activity in SMOi-resistant SI-CSC MBs alters the tumor cell maturation trajectory through enhanced degradation of specific epigenetic regulators, including the histone acetylation machinery. Consequently, SMOi-resistant SI- SMOi-resistant SI-CSC exhibit a global reduction of H3K9Ac, H3K14Ac, H3K56Ac, H4K5Ac, and H4K8Ac marks and gene expression changes. These results provide new insights into how selective pressure on distinct tumor cell populations contributes to different mechanisms of resistance to targeted therapies and implicate histone acetylation in the process. This information can be clinically exploited to understand responses and resistance to SMOis and other targeted therapies. Citation Format: Joshy George, Yaohui Chen, Nourhan Abdelfattah, Keiko Yamamoto, Scott Adamson, Jong Min Choi, Brad Rybinski, Anuj Srivastava, Parveen Kumar, Min Gyu Lee, David S. Baskin, Wen Jiang, Betty Y. Kim, William Flavahan, Jeffrey H. Chuang, Sung Yun Jung, Kyuson Yun. Cancer stem cells, not bulk tumor cells, predict mechanisms of resistance to SMO inhibitors in SHH medulloblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3961.