Cancer Stem Cells, not Bulk Tumor Cells, Determine Mechanisms of Resistance to SMO Inhibitors

Joshy George, Yaohui Chen, Nourhan Abdelfattah, Keiko Yamamoto, Thomas D. Gallup, Scott I. Adamson, Brad Rybinski, Anuj Srivastava, Parveen Kumar, Min Gyu Lee, David S. Baskin, Wen Jiang, Jong Min Choi, William Flavahan, Jeffrey H. Chuang, Betty Y.S. Kim, Susan Xu, Sung Yun Jung, Kyuson Yun

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

The emergence of treatment resistance significantly reduces the clinical utility of many effective targeted therapies. Although both genetic and epigenetic mechanisms of drug resistance have been reported, whether these mechanisms are stochastically selected in individual tumors or governed by a predictable underlying principle is unknown. Here, we report that the dependence of cancer stem cells (CSC), not bulk tumor cells, on the targeted pathway determines the molecular mechanism of resistance in individual tumors. Using both spontaneous and transplantable mouse models of sonic hedgehog (SHH) medulloblastoma treated with a SHH/Smoothened inhibitor (SMOi), sonidegib/LDE225, we show that genetic-based resistance occurs only in tumors that contain SHH-dependent CSCs. In contrast, SHH medulloblastomas containing SHH-dependent bulk tumor cells but SHH-independent CSCs (SI-CSC) acquire resistance through epigenetic reprogramming. Mechanistically, elevated proteasome activity in SMOi-resistant SI-CSC medulloblastomas alters the tumor cell maturation trajectory through enhanced degradation of specific epigenetic regulators, including histone acetylation machinery components, resulting in global reductions in 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. This insight provides a new conceptual framework to understand responses and resistance to SMOis and other targeted therapies. Significance: The mechanism by which individual tumors become resistant to targeted therapies is thought to be unpredictable. This study provides novel insights into how selective pressure on cancer stem versus bulk tumor cells drives distinct and predictable mechanisms of resistance to targeted therapies. This finding paves a way for future treatment strategies that incorporate anticipated resistance mechanisms in devising second-line therapies in a personalized manner.

Original languageEnglish (US)
Pages (from-to)402-416
Number of pages15
JournalCancer research communications
Volume2
Issue number6
DOIs
StatePublished - Jun 2022

ASJC Scopus subject areas

  • Medicine(all)
  • Oncology
  • Cancer Research

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