Repression of BET activity sensitizes oral squamous cell carcinoma to PARP inhibition via inhibiting DNA homologous recombination and immune inhibition

Abstract

Background: To investigate the root cause of therapeutic resistance underlying oral squamous cell carcinoma (OSCC) to the PARP inhibitor olaparib and explore the combination with the BET inhibitor JQ1 to augment its treatment effects.Material and Methods: Cell viability were detected in the study. We also evaluated the expression of a series of factors through quantitative real-time PCR, immunofluorescence and western blot. The effect of combining JQ1 and olaparib in xenograft OSCC mouse model was also examined.Results: The sensitivity of Cal27 cells to olaparib was better than Scc25. 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 activity of combining olaparib with BET inhibitor in OSCC 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 therapy in OSCC.