Bet Protein Inhibitors Prevent Tki-Induced Drug Resistance In Solid Tumors

Acquired drug resistance is one of the major challenges for clinical application of tyrosine kinase inhibitor (TKI) in cancer treatment. TKI-induced drug resistance could develop as a result of adaptive cell reprogramming that leads to pathway feedback activation in the same signaling pathway or parallel pathways or gatekeeper mutations abolishing drug binding. The findings of reversible drug response and lack of genetic mutations in TKI-resistant tumor cells suggest epigenetic basis during resistance development process. Targeting epigenetic modifiers and readers, in particular, the bromodomain and extra-terminal (BET) protein family, has shown promising efficacies against both primary and drug-resistant hematological malignancies via modulating transcription profile and suppressing the MYC oncogene. BGB-3619 is a novel, potent inhibitor of BET family proteins (BRD2, BRD3, BRD4 and BRDT) with IC 50 ranging from 20 to 49 nM. It demonstrates superior anti-proliferation activity than iBET762 in multiple leukemia and lymphoma cell lines. In this study, we investigated the effect of BGB-3619 and iBET762 on solid tumor cells during and after TKI-resistance development. From cell killing assays, BET inhibitors were found to be much more potent to TKI-resistant cells (vemurafenib-resistant A375, HT29, SK-MEL-5, cells and erlotinib-resistant HCC827 cells) than their parental cells. Notably, long-term colony formation assays showed that combination of low dose BET inhibitors and TKI effectively suppressed the expansion of TKI-tolerated cell populations. The enhanced sensitivity of TKI-resistant cells to BET inhibitor was due to strong G1 phase arrest rather than induction of apoptosis. Furthermore, BET inhibitors blocked cell proliferation independent of c-Myc inhibition, suggesting they might affect a broad transcription network and provide favorable epigenetic state to induce cell cycle arrest. Taken together, these findings suggested potential therapeutic activity of BET inhibitor in TKI-resistant solid tumors and a strategy of combining BET inhibitors with TKIs to overcome resistance to targeted cancer therapies. Citation Format: Yuan Zhao, Yiyuan Wu, Hexiang Wang, Bo Ren, Ye Liu, Min Wei, Changyou Zhou, Lusong Luo. BET protein inhibitors prevent TKI-induced drug resistance in solid tumors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4698.