Suppression of adaptive responses to targeted cancer therapy by transcriptional repression
| Autor: | Maria Rusan, Kapsok Li, Wankun Chen, Richard A. Young, Nathanael S. Gray, Tenny Mudianto, Tiffany Tavares, Michael Silkes, Matthew Meyerson, Shuai Li, Bruno Bockorny, Yvonne Y. Li, Kevin A. Buczkowski, Brian J. Abraham, Sook Hee Hong, Tianxia Li, Li Tan, Hideki Terai, Hideo Watanabe, Alan L. Leggett, Ting Chen, Peter S. Hammerman, Camilla L. Christensen, Tae-Jung Kim, Nicholas Kwiatkowski, Kevin Rhee, Yichen Wang, Neermala Poudel-Neupane, Haikuo Zhang, Adam J. Bass, Kwok-Kin Wong, Takeshi Shimamura, Tinghu Zhang |
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| Přispěvatelé: | Massachusetts Institute of Technology. Department of Biology |
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
medicine.medical_treatment Cell Population Biology Bioinformatics Article Targeted therapy 03 medical and health sciences Cell Line Tumor Neoplasms medicine Humans education Ecosystem education.field_of_study Cancer medicine.disease 030104 developmental biology Cell killing medicine.anatomical_structure Oncology Cancer cell Cyclin-dependent kinase 7 Signal transduction Signal Transduction |
| Zdroj: | PMC 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 2018, ' Suppression of adaptive responses to targeted cancer therapy by transcriptional repression ', Cancer Discovery, vol. 8, no. 1, pp. 59-73 . https://doi.org/10.1158/2159-8290.CD-17-0461 |
| DOI: | 10.1158/2159-8290.CD-17-0461 |
| Popis: | 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. ©2017 AACR. See related commentary by Carugo and Draetta, p. 17. This article is highlighted in the In This Issue feature, p. 1 |
| Databáze: | OpenAIRE |
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