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

Elias E. Stratikopoulos, Meaghan Dendy, Matthias Szabolcs, Alan J. Khaykin, Celine Lefebvre, Ming Ming Zhou, Ramon Parsons

Research output: Contribution to journalArticlepeer-review

193 Scopus citations

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.

Original languageEnglish
Pages (from-to)837-851
Number of pages15
JournalCancer Cell
Volume27
Issue number6
DOIs
StatePublished - 8 Jun 2015

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