TY - JOUR
T1 - Cancer Stem Cells, not Bulk Tumor Cells, Determine Mechanisms of Resistance to SMO Inhibitors
AU - George, Joshy
AU - Chen, Yaohui
AU - Abdelfattah, Nourhan
AU - Yamamoto, Keiko
AU - Gallup, Thomas D.
AU - Adamson, Scott I.
AU - Rybinski, Brad
AU - Srivastava, Anuj
AU - Kumar, Parveen
AU - Lee, Min Gyu
AU - Baskin, David S.
AU - Jiang, Wen
AU - Choi, Jong Min
AU - Flavahan, William
AU - Chuang, Jeffrey H.
AU - Kim, Betty Y.S.
AU - Xu, Jiaqiong
AU - Jung, Sung Yun
AU - Yun, Kyuson
N1 - Publisher Copyright:
© 2024 African Science Publications. All rights reserved.
PY - 2022/6
Y1 - 2022/6
N2 - 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.
AB - 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.
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U2 - 10.1158/2767-9764.CRC-22-0124
DO - 10.1158/2767-9764.CRC-22-0124
M3 - Article
C2 - 36688010
AN - SCOPUS:85172668599
SN - 2767-9764
VL - 2
SP - 402
EP - 416
JO - Cancer research communications
JF - Cancer research communications
IS - 6
ER -