Combined targeting poly (ADP-ribose) polymerase and receptor tyrosine kinase inhibits ovarian clear cell carcinoma progression through disrupted ribosome biogenesis

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OCCC has extremely poor prognosis. ARID1A mutation-related chromatin remodeling errors are key molecular features of OCCC. Dysregulation of receptor tyrosine kinases-related signaling pathways is common in OCCC. Here we show that combination of niraparib and lenvatinib exhibits significant synergistic inhibitory effects against platinum-resistant OCCC cell lines, xenografts, patient-derived tumoroid (PDT) models, and prolonged survival in the platinum-refractory patient-derived xenograft (PDX) model. RNA-sequencing revealed the most differently expressed genes in PDX treated with a combination of niraparib and lenvatinib versus control were in structural ribosomal components. Selected differently expressed ribosomal proteins (RPs: RPS2, RPS5, RPS9, and RPL3) was validated using quantitative polymerase chain reaction. Nucleophosmin (NPM1) expression, which is involved in ribosome biogenesis, was inhibited by niraparib and lenvatinib. Our findings imply that combined niraparib and lenvatinib reduces platinum-resistant OCCC progression by attenuating Src phosphorylation, NPM1 expression and ribosome biogenesis. These results highlight the necessity for continued exploration of this promising treatment strategy, particularly in future clinical trials for platinum-resistant or platinum-refractory OCCC. KEY MESSAGES: The combination of niraparib and lenvatinib synergistically inhibits platinum-resistant OCCC. This combination prolongs survival in a platinum-refractory PDX model. RNA sequencing revealed that the most differentially expressed genes in PDX models treated with this combination were associated with structural ribosomal components. This combination suppresses Src phosphorylation, NPM1 expression, and ribosomal protein levels in OCCC.

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