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Multi-Omics Profiling Establishes the Polypharmacology of FDA Approved CSK4/6 Inhibitors and Its Impact on Drug Response

61 Pages Posted: 17 Nov 2018 Sneak Peek Status: Published

See all articles by Marc Hafner

Marc Hafner

Harvard University - Department of Systems Biology

Caitlin E. Mills

Harvard University - Laboratory of Systems Pharmacology

Kartik Subramanian

Harvard University - Laboratory of Systems Pharmacology

Chen Chen

Harvard University - Laboratory of Systems Pharmacology

Mirra Chung

Harvard University - Laboratory of Systems Pharmacology

Sarah A. Boswell

Harvard University - Laboratory of Systems Pharmacology

Robert A. Everley

Harvard University - Laboratory of Systems Pharmacology

Changchang Liu

Harvard University - Laboratory of Systems Pharmacology

Charlotte S. Walmsley

Harvard University - Termeer Center for Targeted Therapies

Dejan Juric

Harvard University - Laboratory of Systems Pharmacology

Peter K. Sorger

Harvard University - Laboratory of Systems Pharmacology

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Abstract

The target profiles of many drugs are established early in their development and are not systematically revisited at the time of approval, raising the question whether human therapeutics with the same nominal targets but different chemical structures are functionally equivalent. In this paper we use five distinct phenotypic and biochemical assays to compare approved inhibitors of the cyclindependent kinases CDK4/6 (palbociclib, ribociclib, and abemaciclib) that are promising therapies for hormone-receptor positive breast cancer. We find that transcriptional, proteomic and phenotypic changes induced by the three drugs differ significantly and that abemaciclib has activates overlapping those of the older generation CDK inhibitor alvocidib. Abemaciclib’s activities arise from inhibition of kinases other than CDK4/6 including CDK2/Cyclin A/E and CDK1/Cyclin B. Our data suggest the potential for differential use in the clinic and argue that a multi-faceted experimental and computational approach is necessary to obtain a reliable picture of kinase inhibitor target spectrum.

Keywords: Therapeutics, targeted therapy; HR breast cancer; CDK4/6 inhibitors; drug profiling; drug mechanisms of action

Suggested Citation

Hafner, Marc and Mills, Caitlin E. and Subramanian, Kartik and Chen, Chen and Chung, Mirra and Boswell, Sarah A. and Everley, Robert A. and Liu, Changchang and Walmsley, Charlotte S. and Juric, Dejan and Sorger, Peter K., Multi-Omics Profiling Establishes the Polypharmacology of FDA Approved CSK4/6 Inhibitors and Its Impact on Drug Response (November 16, 2018). Available at SSRN: https://ssrn.com/abstract=3285804 or http://dx.doi.org/10.2139/ssrn.3285804
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Marc Hafner

Harvard University - Department of Systems Biology

Boston,, MA 02115
United States

Caitlin E. Mills

Harvard University - Laboratory of Systems Pharmacology

MA
United States

Kartik Subramanian

Harvard University - Laboratory of Systems Pharmacology

MA
United States

Chen Chen

Harvard University - Laboratory of Systems Pharmacology

MA
United States

Mirra Chung

Harvard University - Laboratory of Systems Pharmacology

MA
United States

Sarah A. Boswell

Harvard University - Laboratory of Systems Pharmacology

MA
United States

Robert A. Everley

Harvard University - Laboratory of Systems Pharmacology

MA
United States

Changchang Liu

Harvard University - Laboratory of Systems Pharmacology

MA
United States

Charlotte S. Walmsley

Harvard University - Termeer Center for Targeted Therapies

55 Fruit Street Boston
Boston, MA 02114
United States

Dejan Juric

Harvard University - Laboratory of Systems Pharmacology

MA
United States

Peter K. Sorger (Contact Author)

Harvard University - Laboratory of Systems Pharmacology ( email )

MA
United States

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