Suppression of adaptive responses to targeted cancer therapy by transcriptional repression
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE89129 | GEO | 2017/10/23
SECONDARY ACCESSION(S): PRJNA350331
REPOSITORIES: GEO
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Project description: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. 17This article is highlighted in the In This Issue feature, p. 1.
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Project description:Large-scale genomic profiling efforts have facilitated the characterization of molecular alterations in cancers and aided the development of targeted kinase inhibitors for a wide array of cancer types. However, resistance to these targeted therapies invariably develops and limits their clinical efficacy. Targeting tumours with kinase inhibitors induces complex adaptive survival programs that promote the persistence of a fraction of the original cancer cell population, facilitating the eventual outgrowth of inhibitor-resistant tumour clones following clonal evolution. Here we show that the addition of a newly identified transcriptional repressor, THZ1, to targeted cancer therapy enhances cell killing and impedes the emergence of drug-resistant cell populations in cellular and in vivo cancer models with diverse genetic dependencies. We propose that targeted therapy induces a state of transcriptional dependency in a subpopulation of cells poised to become drug tolerant. THZ1 can exploit this dependency by blocking dynamic transcriptional responses, remodelling of enhancers and key signalling outputs required for tumour cell survival in the setting of targeted cancer therapies. These findings suggest that the addition of THZ1 to targeted cancer therapies is a promising broad-based strategy to hinder the emergence of drug-resistant cancer cell populations.
2017-10-23 | GSE89128 | GEO
Project description:Large-scale genomic profiling efforts have facilitated the characterization of molecular alterations in cancers and aided the development of targeted kinase inhibitors for a wide array of cancer types. However, resistance to these targeted therapies invariably develops and limits their clinical efficacy. Targeting tumours with kinase inhibitors induces complex adaptive survival programs that promote the persistence of a fraction of the original cancer cell population, facilitating the eventual outgrowth of inhibitor-resistant tumour clones following clonal evolution. Here we show that the addition of a newly identified transcriptional repressor, THZ1, to targeted cancer therapy enhances cell killing and impedes the emergence of drug-resistant cell populations in cellular and in vivo cancer models with diverse genetic dependencies. We propose that targeted therapy induces a state of transcriptional dependency in a subpopulation of cells poised to become drug tolerant. THZ1 can exploit this dependency by blocking dynamic transcriptional responses, remodelling of enhancers and key signalling outputs required for tumour cell survival in the setting of targeted cancer therapies. These findings suggest that the addition of THZ1 to targeted cancer therapies is a promising broad-based strategy to hinder the emergence of drug-resistant cancer cell populations.
2017-10-23 | GSE89127 | GEO
Project description:Suppression of adaptive responses to targeted cancer therapy by transcriptional repression
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Project description:Certain RGD-binding integrins are required for cell adhesion, migration, and proliferation and are overexpressed in most tumors, making them attractive therapeutic targets. However, multiple integrin antagonist drug candidates have failed to show efficacy in cancer clinical trials. In this work, we instead exploit these integrins as a target for antibody Fc effector functions in the context of cancer immunotherapy. By combining administration of an engineered mouse serum albumin/IL-2 fusion with an Fc fusion to an integrin-binding peptide (2.5F-Fc), significant survival improvements are achieved in three syngeneic mouse tumor models, including complete responses with protective immunity. Functional integrin antagonism does not contribute significantly to efficacy; rather, this therapy recruits both an innate and adaptive immune response, as deficiencies in either arm result in reduced tumor control. Administration of this integrin-targeted immunotherapy together with an anti-PD-1 antibody further improves responses and predominantly results in cures. Overall, this well-tolerated therapy achieves tumor specificity by redirecting inflammation to a functional target fundamental to tumorigenic processes but expressed at significantly lower levels in healthy tissues, and it shows promise for translation.
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