TY - JOUR
T1 - Suppression of adaptive responses to targeted cancer therapy by transcriptional repression
AU - Rusan, Maria
AU - Li, Kapsok
AU - Li, Yvonne
AU - Christensen, Camilla L.
AU - Abraham, Brian J.
AU - Kwiatkowski, Nicholas
AU - Buczkowski, Kevin A.
AU - Bockorny, Bruno
AU - Chen, Ting
AU - Li, Shuai
AU - Rhee, Kevin
AU - Zhang, Haikuo
AU - Chen, Wankun
AU - Terai, Hideki
AU - Tavares, Tiffany
AU - Leggett, Alan L.
AU - Li, Tianxia
AU - Wang, Yichen
AU - Zhang, Tinghu
AU - Kim, Tae Jung
AU - Hong, Sook Hee
AU - Poudel-Neupane, Neermala
AU - Silkes, Michael
AU - Mudianto, Tenny
AU - Tan, Li
AU - Shimamura, Takeshi
AU - Meyerson, Matthew
AU - Bass, Adam J.
AU - Watanabe, Hideo
AU - Gray, Nathanael S.
AU - Young, Richard A.
AU - Wong, Kwok Kin
AU - Hammerman, Peter S.
N1 - Publisher Copyright:
© 2017 American Association for Cancer Research.
PY - 2018/1
Y1 - 2018/1
N2 - Acquired drug resistance is a major factor limiting the effectiveness of targeted cancer therapies. Targeting tumors with kinase inhibitors induces complex adap- tive programs that promote the persistence of a fraction of the original cell population, facilitating the eventual outgrowth of inhibitor-resistant tumor clones. We show that the addition of a newly identified CDK7/12 inhibitor, THZ1, to targeted therapy enhances cell killing and impedes the emergence of drug-resistant cell populations in diverse cellular and in vivo cancer models. We propose that targeted therapy induces a state of transcriptional dependency in a subpopulation of cells poised to become drug tolerant, which THZ1 can exploit by blocking dynamic transcriptional responses, promoting remodeling of enhancers and key signaling outputs required for tumor cell survival in the setting of targeted therapy. These findings suggest that the addition of THZ1 to targeted therapies is a promising broad-based strategy to hinder the emergence of drug-resistant cancer cell populations. SIGNIFICANCE: CDK7/12 inhibition prevents active enhancer formation at genes, promoting resistance emergence in response to targeted therapy, and impedes the engagement of transcriptional programs required for tumor cell survival. CDK7/12 inhibition in combination with targeted cancer therapies may serve as a therapeutic paradigm for enhancing the effectiveness of targeted therapies.
AB - Acquired drug resistance is a major factor limiting the effectiveness of targeted cancer therapies. Targeting tumors with kinase inhibitors induces complex adap- tive programs that promote the persistence of a fraction of the original cell population, facilitating the eventual outgrowth of inhibitor-resistant tumor clones. We show that the addition of a newly identified CDK7/12 inhibitor, THZ1, to targeted therapy enhances cell killing and impedes the emergence of drug-resistant cell populations in diverse cellular and in vivo cancer models. We propose that targeted therapy induces a state of transcriptional dependency in a subpopulation of cells poised to become drug tolerant, which THZ1 can exploit by blocking dynamic transcriptional responses, promoting remodeling of enhancers and key signaling outputs required for tumor cell survival in the setting of targeted therapy. These findings suggest that the addition of THZ1 to targeted therapies is a promising broad-based strategy to hinder the emergence of drug-resistant cancer cell populations. SIGNIFICANCE: CDK7/12 inhibition prevents active enhancer formation at genes, promoting resistance emergence in response to targeted therapy, and impedes the engagement of transcriptional programs required for tumor cell survival. CDK7/12 inhibition in combination with targeted cancer therapies may serve as a therapeutic paradigm for enhancing the effectiveness of targeted therapies.
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U2 - 10.1158/2159-8290.CD-17-0461
DO - 10.1158/2159-8290.CD-17-0461
M3 - Article
C2 - 29054992
AN - SCOPUS:85042195320
VL - 8
SP - 59
EP - 73
JO - Cancer Discovery
JF - Cancer Discovery
SN - 2159-8274
IS - 1
ER -