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Cancer Cell. 2015 Jun 8;27(6):837-51. doi: 10.1016/j.ccell.2015.05.006.

Kinase and BET Inhibitors Together Clamp Inhibition of PI3K Signaling and Overcome Resistance to Therapy.

Author information

1
Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, 1470 Madison Avenue, New York, NY 10029, USA.
2
Department of Pathology, Columbia University Medical Center, New York, NY 10032, USA.
3
Inserm U981, Institut Gustave Roussy, 94805 Villejuif, France.
4
Department of Structural and Chemical Biology, Icahn School of Medicine at Mount Sinai, 1470 Madison Avenue, New York, NY 10029, USA.
5
Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, 1470 Madison Avenue, New York, NY 10029, USA. Electronic address: ramon.parsons@mssm.edu.

Abstract

Unsustained enzyme inhibition is a barrier to targeted therapy for cancer. Here, resistance to a class I PI3K inhibitor in a model of metastatic breast cancer driven by PI3K and MYC was associated with feedback activation of tyrosine kinase receptors (RTKs), AKT, mTOR, and MYC. Inhibitors of bromodomain and extra terminal domain (BET) proteins also failed to affect tumor growth. Interestingly, BET inhibitors lowered PI3K signaling and dissociated BRD4 from chromatin at regulatory regions of insulin receptor and EGFR family RTKs to reduce their expression. Combined PI3K and BET inhibition induced cell death, tumor regression, and clamped inhibition of PI3K signaling in a broad range of tumor cell lines to provide a strategy to overcome resistance to kinase inhibitor therapy.

PMID:
26058079
PMCID:
PMC4918409
DOI:
10.1016/j.ccell.2015.05.006
[Indexed for MEDLINE]
Free PMC Article

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