Dual PI3K and BET inhibition prevents PI3K reactivation and inhibits the growth of multiple tumor types.
Major finding: Dual PI3K and BET inhibition prevents PI3K reactivation and inhibits the growth of multiple tumor types.
Mechanism: BET inhibition attenuates the expression of RTKs by blocking BRD4 binding to regulatory regions.
Impact: Combined PI3K and BET blockade may be exploited to circumvent resistance to kinase inhibitor therapy.
Pharmacologic inhibition of PI3K signaling is effective in cancers with activating mutations in the PI3K pathway. However, many of these tumors exhibit intrinsic resistant to treatment, in part due to feedback activation of upstream receptor tyrosine kinases (RTK), emphasizing the need to develop combinatorial therapeutic strategies. Stratikopoulos and colleagues demonstrated that somatic activation of PI3K cooperated with MYC to drive tumorigenesis in mouse models of metastatic breast cancer. Cell lines derived from these tumors were resistant to single-agent treatment with either the pan–class I PI3K inhibitor GDC-0941 or BET inhibitors such as JQ1 due to incomplete suppression of AKT signaling; similar resistance was observed in a human breast cancer line harboring mutant PIK3CA and MYC amplification. The combination of PI3K and BET inhibition significantly reduced tumor cell growth and increased apoptosis, indicating that BET inhibition sensitizes resistant cells to PI3K blockade. Addition of a BET inhibitor to GDC-0941–treated cell lines of diverse tumor types prevented feedback reactivation of the PI3K pathway, including AKT, mTOR, and MYC, and suppressed the transcription of genes encoding numerous RTKs that were induced by PI3K inhibition alone, including EGFR, insulin-like growth factor 1 receptor, HER2, HER3, and insulin receptor. Chromatin immunoprecipitation analysis revealed that BET inhibitor treatment blocked bromodomain-containing 4 (BRD4) from binding to regulatory regions within the genes encoding these RTKs, demonstrating a direct role of BET proteins in regulating PI3K signaling and resistance to PI3K inhibition. Furthermore, dual PI3K/BET inhibition was effective in reducing growth and inducing apoptosis across multiple cancer types, and induced mammary tumor regression in vivo. These data identify BET proteins as mediators of feedback RTK signaling that drives therapeutic resistance to kinase inhibitor therapy and illustrate the applicability of combined PI3K/BET inhibition as a means to broadly overcome this resistance.