Suppression of Adaptive Responses to Targeted Cancer Therapy by Transcriptional Repression Journal Article

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Authors: Rusan, M.; Li, K.; Li, Y; Christensen, C. L.; Abraham, B. J.; Kwiatkowski, N.; Buczkowski, K. A.; Bockorny, B.; Chen, T.; Li, S; Rhee, K.; Zhang, H; Chen, W.; Terai, H.; Tavares, T.; Leggett, A. L.; Li, T.; Wang, Y; Zhang, T.; Kim, T. J.; Hong, S. H.; Poudel-Neupane, N.; Silkes, M.; Mudianto, T.; Tan, L.; Shimamura, T; Meyerson, M.; Bass, A. J.; Watanabe, H.; Gray, N. S.; Young, R. A.; Wong, K. K.; Hammerman, P. S.
Article Title: Suppression of Adaptive Responses to Targeted Cancer Therapy by Transcriptional Repression
Abstract: Acquired drug resistance is a major factor limiting the effectiveness of targeted cancer therapies. Targeting tumors with kinase inhibitors induces complex adaptive 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. Cancer Discov; 8(1); 59-73. (c)2017 AACR.See related commentary by Carugo and Draetta, p. 17This article is highlighted in the In This Issue feature, p. 1.
Journal Title: Cancer discovery
Volume: 8
Issue: 1
ISSN: 2159-8290; 2159-8274
Publisher: American Association for Cancer Research  
Journal Place: United States
Date Published: 2018
Start Page: 59
End Page: 73
Language: eng
DOI/URL:

10.1158/2159-8290.CD-17-0461
Notes: LR: 20180222; CI: (c)2017; GR: R01 CA196932/CA/NCI NIH HHS/United States; GR: R01 CA122794/CA/NCI NIH HHS/United States; GR: K08 CA163677/CA/NCI NIH HHS/United States; GR: R01 CA179483/CA/NCI NIH HHS/United States; GR: P01 CA154303/CA/NCI NIH HHS/United States; GR: R01 CA163896/CA/NCI NIH HHS/United States; GR: R01 CA166480/CA/NCI NIH HHS/United States; GR: R01 CA140594/CA/NCI NIH HHS/United States; GR: U01 CA213333/CA/NCI NIH HHS/United States; JID: 101561693; NIHMS915227; PMCR: 2019/01/01 00:00; 2017/05/01 00:00 [received]; 2017/10/02 00:00 [revised]; 2017/10/17 00:00 [accepted]; 2019/01/01 00:00 [pmc-release]; 2017/10/22 06:00 [pubmed]; 2017/10/22 06:00 [medline]; 2017/10/22 06:00 [entrez]; ppublish