Hitting two oncogenic machineries in cancer cells: cooperative effects of the multi-kinase inhibitor ponatinib and the BET bromodomain blockers JQ1 or dBET1 on human carcinoma cells.

In recent years, numerous new targeted drugs, including multi-kinase inhibitors and epigenetic modulators have been developed for cancer treatment. Ponatinib blocks a variety of tyrosine kinases including ABL and fibroblast growth factor receptor (FGFR), and the BET bromodomain (BRD) antagonists JQ1 and dBET1 impede MYC oncogene expression. Both drugs have demonstrated substantial anti-cancer efficacy against several hematological malignancies. Solid tumors, on the other hand, although frequently driven by FGFR and/or MYC, are often unresponsive to these drugs. This is due, at least in part, to compensatory feedback-loops in the kinome and transcription network of these tumors, which are activated in response to drug exposure. Therefore, we hypothesized that the combination of the multi-kinase inhibitor ponatinib with transcription modulators such as JQ1 or dBET1 might overcome this therapeutic recalcitrance. Using (3)H-thymidine uptake, cell cycle analysis, and caspase-3 or Annexin V labeling, we demonstrate that single drugs induce moderate dose-dependent growth-inhibition and/or apoptosis in colon (HCT116, HT29), breast (MCF-7, SKBR3) and ovarian (A2780, SKOV3) cancer cells. Ponatinib elicited primarily apoptosis, while JQ1 and dBET1 caused G0/G1 cell cycle arrest and very mild cell death. Phospho-FGFR and MYC, major targets of ponatinib and BET inhibitors, were downregulated after treatment with single drugs. Remarkably, ponatinib was found to sensitize cells to BET antagonists by enhancing apoptotic cell death, and this effect was associated with downregulation of MYC. In summary, our data shows that ponatinib sensitizes colon, breast, and ovarian cancer cells to BET bromodomain inhibitors. Further studies are warranted to determine the clinical value of this phenomenon.