Deciphering Clonal Somatic Alterations Associated with Homologous Recombination Deficiency and Synthetic Lethality in Mesothelioma

Mesothelioma is a rare and incurable form of cancer that arises in the the parietal pleura. With limited treatment options, particularly in the relapsed setting, there is a need to identify novel precision medicines that exploit genetic differences. Homologous recombination deficiency (HRD) is often present in mesothelioma, where a synthetically lethal relationship can be formed by treating with PARP inhibitors (PARPi). With no current biomarker of sensitivity, this current study aimed to explore the promise of PARPi treatment in mesothelioma and understand the causations of sensitivity.

Ex vivo mesothelioma patient-derived explants (PDEs) were treated with varying doses of the PARPi rucaparib and niraparib. Multiplex immunofluorescence (mIF) staining showed PARPi can induce double-strand break (DSB) formation and cell death, and proposed responses of the targeted treatment. DNA damage response (DDR) related genes and SLFN11 were shown not to predict PARPi sensitivity, despite expectations.

While, transcriptomic data showed inflammatory responses, primarily IFN-α and IFN-γ responses, were significantly associated with PARPi responders across all mesothelioma models following gene set enrichment analysis (GSEA). Given that PARPi are proinflammatory this provides a plausible explanation as to why these pathways were upregulated, providing a favourable environment for response. This also supports the combination of PARPi with immune checkpoint inhibitors (ICIs), providing a synergistic relationship to increase the therapeutic efficacy of both drugs. Moreover, these findings have shown that PARPi are a feasible option as a novel second-line therapy in the relapsed setting of mesothelioma, with potential to use cisplatin response as a surrogate of sensitivity based on some of these results.