Repression of BET activity sensitizes oral squamous cell carcinoma to PARP inhibition via inhibiting DNA homologous recombination and immune inhibition
Abstract Objective: To investigate the therapeutic resistance mechanism of oral squamous cell carcinoma (OSCC) to the PARP inhibitor olaparib and explore the combination with the BET inhibitor JQ1 to enhance its treatment effects. Material and Methods: Cell proliferation, apoptosis and cell cycle distribution were evaluated. Levels of relevant factors were determined by quantitative real-time PCR, western blot and immunofluorescence. The effect of the combination treatment on xenograft OSCC mouse model was examined.Results: Cal27 cells were more sensitive to the PARP inhibitor olaparib than Scc25 cells. Functional assays demonstrated that olaparib induced HR repair and upregulated PD-L1 expression, which results in drug resistance of OSCC to olaparib. Variations of these factors in the two cell lines may explain different sensitivity to olaparib. Moreover, the JQ1 BET inhibitor and olaparib synergistically exhibited anti-cancer effects in OSCC in vitro and in vivo and inhibited essential HR repair factors RAD51, BRCA1, and TOPBP1 through the ATR/CHK1 pathway and immune suppression mediated by the PD-L1 pathway.Conclusions: Elevated HR and PD-L1 are involved in resistance mechanisms of OSCC to olaparib, attenuating its anti-tumor effects. Our results suggest that the strong synergistic anti-cancer effects of the combination of olaparib with the JQ1 BET inhibitor in OSCC in vitro and in vivo may be via suppression of the ATR/CHK1-mediated DNA damage response and PD-L1-related immune escape, indicating this combination strategy as a possible therapeutic approach for OSCC.