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Cancer Stem Cells, not Bulk Tumor Cells, Determine Mechanisms of Resistance to SMO Inhibitors
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 pre...
Autores principales: | , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Association for Cancer Research
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9853917/ https://www.ncbi.nlm.nih.gov/pubmed/36688010 http://dx.doi.org/10.1158/2767-9764.CRC-22-0124 |
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author | George, Joshy Chen, Yaohui Abdelfattah, Nourhan Yamamoto, Keiko Gallup, Thomas D. Adamson, Scott I. Rybinski, Brad Srivastava, Anuj Kumar, Parveen Lee, Min Gyu Baskin, David S. Jiang, Wen Choi, Jong Min Flavahan, William Chuang, Jeffrey H. Kim, Betty Y.S. Xu, Jiaqiong Jung, Sung Yun Yun, Kyuson |
author_facet | George, Joshy Chen, Yaohui Abdelfattah, Nourhan Yamamoto, Keiko Gallup, Thomas D. Adamson, Scott I. Rybinski, Brad Srivastava, Anuj Kumar, Parveen Lee, Min Gyu Baskin, David S. Jiang, Wen Choi, Jong Min Flavahan, William Chuang, Jeffrey H. Kim, Betty Y.S. Xu, Jiaqiong Jung, Sung Yun Yun, Kyuson |
author_sort | George, Joshy |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-9853917 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | American Association for Cancer Research |
record_format | MEDLINE/PubMed |
spelling | pubmed-98539172023-01-20 Cancer Stem Cells, not Bulk Tumor Cells, Determine Mechanisms of Resistance to SMO Inhibitors George, Joshy Chen, Yaohui Abdelfattah, Nourhan Yamamoto, Keiko Gallup, Thomas D. Adamson, Scott I. Rybinski, Brad Srivastava, Anuj Kumar, Parveen Lee, Min Gyu Baskin, David S. Jiang, Wen Choi, Jong Min Flavahan, William Chuang, Jeffrey H. Kim, Betty Y.S. Xu, Jiaqiong Jung, Sung Yun Yun, Kyuson Cancer Res Commun Research Article 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. American Association for Cancer Research 2022-06-06 /pmc/articles/PMC9853917/ /pubmed/36688010 http://dx.doi.org/10.1158/2767-9764.CRC-22-0124 Text en © 2022 The Authors; Published by the American Association for Cancer Research https://creativecommons.org/licenses/by/4.0/This open access article is distributed under the Creative Commons Attribution 4.0 International (CC BY 4.0) license. |
spellingShingle | Research Article George, Joshy Chen, Yaohui Abdelfattah, Nourhan Yamamoto, Keiko Gallup, Thomas D. Adamson, Scott I. Rybinski, Brad Srivastava, Anuj Kumar, Parveen Lee, Min Gyu Baskin, David S. Jiang, Wen Choi, Jong Min Flavahan, William Chuang, Jeffrey H. Kim, Betty Y.S. Xu, Jiaqiong Jung, Sung Yun Yun, Kyuson Cancer Stem Cells, not Bulk Tumor Cells, Determine Mechanisms of Resistance to SMO Inhibitors |
title | Cancer Stem Cells, not Bulk Tumor Cells, Determine Mechanisms of Resistance to SMO Inhibitors |
title_full | Cancer Stem Cells, not Bulk Tumor Cells, Determine Mechanisms of Resistance to SMO Inhibitors |
title_fullStr | Cancer Stem Cells, not Bulk Tumor Cells, Determine Mechanisms of Resistance to SMO Inhibitors |
title_full_unstemmed | Cancer Stem Cells, not Bulk Tumor Cells, Determine Mechanisms of Resistance to SMO Inhibitors |
title_short | Cancer Stem Cells, not Bulk Tumor Cells, Determine Mechanisms of Resistance to SMO Inhibitors |
title_sort | cancer stem cells, not bulk tumor cells, determine mechanisms of resistance to smo inhibitors |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9853917/ https://www.ncbi.nlm.nih.gov/pubmed/36688010 http://dx.doi.org/10.1158/2767-9764.CRC-22-0124 |
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