Document Type
Article
Publication Date
6-1-2022
Original Citation
George J,
Chen Y,
Abdelfattah N,
Yamamoto K,
Gallup T,
Adamson S,
Rybinski B,
Srivastava A,
Kumar P,
Lee M,
Baskin D,
Jiang W,
Choi J,
Flavahan W,
Chuang J,
Kim B,
Xu J,
Jung S,
Yun K.
Cancer stem cells, not bulk tumor cells, determine mechanisms of resistance to SMO inhibitors. Cancer Res Commun. 2022;2(6):402-16.
Keywords
JGM, JMG
JAX Source
Cancer Res Commun. 2022;2(6):402-16.
ISSN
2767-9764
PMID
36688010
DOI
https://doi.org/10.1158/2767-9764.crc-22-0124
Grant
This study was supported by the American Brain Tumor Association Dis- covery Award, the Department of Defense (W81XWH-14-1-0115), the Cancer Prevention and Research Institute of Texas (CPRIT; RP180882), and The Don- aldson Charitable Foundation, to K. Yun. It was also supported by Donna and Kenneth Peak, The Kenneth R. Peak Foundation, The John S. Dunn Founda- tion, The Taub Foundation, The Blanche Green Fund of the Pauline Sterne Wolff Memorial Foundation, The Kelly Kicking Cancer Foundation, The Methodist Hospital Foundation & The Veralan Foundation to D. Baskin. It was also supported by the Jackson Laboratory Cancer Center fund (P30CA034196). J.H. Chuang was funded by the NCI award numbers P30CA034196 and R21CA191848. M.G. Lee was supported by grants from the Cancer Prevention and Research Institute of Texas (CPRIT; RP140271), the NIH (R01CA157919, R01CA207098, and R01CA207109), and the Center for Cancer Epigenetics at MD Anderson. N. Abdelfattah was supported by the DOD Horizon Award (CA191052).
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 (CSCs), 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 (MB) treated with an SHH/Smoothened inhibitor, sonidegib/LDE225, we show that genetic-based resistance occurs only in tumors that contain SHH-dependent CSCs (SD-CSCs). In contrast, SHH MBs containing SHH-dependent bulk tumor cells but SHH-independent CSCs (SI-CSCs) acquire resistance through epigenetic reprogramming. Mechanistically, elevated proteasome activity in SMOi-resistant SI-CSC MBs 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.
Comments
This open access article is distributed under the Creative Commons Attribution 4.0
International (CC BY 4.0) license.