Novel Class I HDAC Inhibitors Sensitize Ovarian Cancer Cells for Cisplatin and Niraparib via an HDAC3-SLFN11 Axis

Abstract

The DNA/RNA helicase Schlafen11 (SLFN11) is considered a sensitivity marker of various tumor cells for cytotoxic treatment with DNA damaging agents (DDA), such as cisplatin and PARP inhibitors (PARPi). Cells can epigenetically silence SLFN11 expression to gain chemoresistance, which can be targeted by HDAC inhibitors (HDACi). Here, we investigate the predictive value of SLFN11 expression for the response to three different PARPi in ovarian cancer cells. Furthermore, we target its epigenetic downregulation via HDACi for sensitization to cisplatin and PARPi. We show that HDAC3 plays a key role in SLFN11 silencing in W1 and W1CR ovarian cancer cells, confirmed by an HDAC3 knockdown approach. Therefore, addressing HDAC3 by novel class I HDACi DS-103 and FL-007 at non-toxic concentrations restored SLFN11 expression with various consequences for DDA treatment in W1, W1CR, and SKOV-3 cells. While DS-103 and FL-007 significantly sensitized cisplatin-resistant W1CR cells to cisplatin to the level of W1 cells, the response to various PARPi remains divergent. Whereas both HDACi induced significant sensitization in W1 and W1CR cells, and DS-103 in SKOV-3 cells for niraparib cytotoxicity, cells remain unaffected in response to olaparib and rucaparib. Both compounds were also shown to be less dependent on, or independent of, SLFN11 in different ovarian cancer cells. In sum, the first time reported functional link of HDAC3 and SLFN11 appears an attractive co-treatment opportunity of DDA with HDACi. This is particularly promising for niraparib as it has a broader approval independent of BRCA status compared to other PARPi.