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Targeting Vulnerabilities in Successive Cell Cycle Stages to Induce Death of PI3K-Activated Basal-Like Breast Cancer Cells

63 Pages Posted: 31 Oct 2018 Sneak Peek Status: Under Review

See all articles by Sameer S. Chopra

Sameer S. Chopra

Harvard University - Laboratory of Systems Pharmacology

Anne Jenney

Harvard University - Laboratory of Systems Pharmacology

Adam C. Palmer

Harvard University - Laboratory of Systems Pharmacology

Mario Niepel

Harvard University - Laboratory of Systems Pharmacology

Caitlin Mills

Harvard University - Laboratory of Systems Pharmacology

Sindhu Carmen Sivakumaren

Harvard University - Department of Biological Chemistry and Molecular Pharmacology

Qingsong Liu

Harvard University - Department of Biological Chemistry and Molecular Pharmacology

Nathanael S. Gray

Harvard University - Department of Biological Chemistry and Molecular Pharmacology

Peter K. Sorger

Harvard University - Laboratory of Systems Pharmacology

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Abstract

Frequent mutation of PI3K pathway genes in human tumors has stimulated large investments in therapeutic drugs targeting this pathway but clinical successes have been rare. As a result, many cancers with high PI3K pathway activity are still treated with conventional chemotherapy. By systematically analyzing responses of basal-like breast cancer cells to PI3K pathway inhibitors, we show that one drug, Torin2, is unusually effective because it inhibits both mTOR and PI3K-like kinases (PIKKs). Experiments with Torin2 and combinations of selective kinase inhibitors demonstrate that submaximal G1/S inhibition, increased S phase replication stress, and single-stranded DNA in mitosis are all involved in cell killing. Combination therapy with inhibitors of signal transduction kinases conventionally targets simultaneously active pathways. Our studies of Torin2 show that favorable combinatorial drug effects can also result from targeting successive cell cycle vulnerabilities, eliciting a cascade of deleterious effects that culminates in mitotic errors and death.

Suggested Citation

Chopra, Sameer S. and Jenney, Anne and Palmer, Adam C. and Niepel, Mario and Mills, Caitlin and Sivakumaren, Sindhu Carmen and Liu, Qingsong and Gray, Nathanael S. and Sorger, Peter K., Targeting Vulnerabilities in Successive Cell Cycle Stages to Induce Death of PI3K-Activated Basal-Like Breast Cancer Cells (Octover 30, 2018). Available at SSRN: https://ssrn.com/abstract=3275287 or http://dx.doi.org/10.2139/ssrn.3275287
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Sameer S. Chopra (Contact Author)

Harvard University - Laboratory of Systems Pharmacology

MA
United States

Anne Jenney

Harvard University - Laboratory of Systems Pharmacology

MA
United States

Adam C. Palmer

Harvard University - Laboratory of Systems Pharmacology

MA
United States

Mario Niepel

Harvard University - Laboratory of Systems Pharmacology

MA
United States

Caitlin Mills

Harvard University - Laboratory of Systems Pharmacology

MA
United States

Sindhu Carmen Sivakumaren

Harvard University - Department of Biological Chemistry and Molecular Pharmacology

250 Longwood Avenue
Boston, MA 02115
United States

Qingsong Liu

Harvard University - Department of Biological Chemistry and Molecular Pharmacology

250 Longwood Avenue
Boston, MA 02115
United States

Nathanael S. Gray

Harvard University - Department of Biological Chemistry and Molecular Pharmacology

250 Longwood Avenue
Boston, MA 02115
United States

Peter K. Sorger

Harvard University - Laboratory of Systems Pharmacology ( email )

MA
United States

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