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Cell Syst. 2020 Jan 22;10(1):66-81.e11. doi: 10.1016/j.cels.2019.11.001. Epub 2019 Dec 4.

Torin2 Exploits Replication and Checkpoint Vulnerabilities to Cause Death of PI3K-Activated Triple-Negative Breast Cancer Cells.

Author information

1
Laboratory of Systems Pharmacology, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA; Harvard Ludwig Center, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA; Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, MA 02215, USA.
2
Laboratory of Systems Pharmacology, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA; Harvard Ludwig Center, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA.
3
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA; Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, MA 02215, USA.
4
Laboratory of Systems Pharmacology, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA.
5
Division of Signal Transduction, Beth Israel Deaconess Medical Center, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA.
6
Laboratory of Systems Pharmacology, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA; Harvard Ludwig Center, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA. Electronic address: peter_sorger@hms.harvard.edu.

Abstract

Frequent mutation of PI3K/AKT/mTOR signaling pathway genes in human cancers has stimulated large investments in targeted drugs but clinical successes are rare. As a result, many cancers with high PI3K pathway activity, such as triple-negative breast cancer (TNBC), are treated primarily with chemotherapy. By systematically analyzing responses of TNBC cells to a diverse collection of PI3K pathway inhibitors, we find that one drug, Torin2, is unusually effective because it inhibits both mTOR and other PI3K-like kinases (PIKKs). In contrast to mTOR-selective inhibitors, Torin2 exploits dependencies on several kinases for S-phase progression and cell-cycle checkpoints, thereby causing accumulation of single-stranded DNA and death by replication catastrophe or mitotic failure. Thus, Torin2 and its chemical analogs represent a mechanistically distinct class of PI3K pathway inhibitors that are uniquely cytotoxic to TNBC cells. This insight could be translated therapeutically by further developing Torin2 analogs or combinations of existing mTOR and PIKK inhibitors.

KEYWORDS:

ATR/Chk1; PI3K/AKT/mTOR; Torin2; cell cycle; mitotic catastrophe; polypharmacology; replication catastrophe; replication stress; small molecule drugs; triple-negative breast cancer

PMID:
31812693
PMCID:
PMC7000271
[Available on 2021-01-22]
DOI:
10.1016/j.cels.2019.11.001
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