778P - Combined targeting poly (ADP-ribose) polymerase and receptor tyrosine kinase inhibits ovarian clear cell carcinoma progression via disrupted ribosomal biogenesis

Background

Advanced ovarian clear cell carcinoma (OCCC) has extremely poor prognosis. AT-rich interactive domain 1A (ARID1A) mutation-related chromatin remodeling errors are key molecular features of OCCC. Dysregulated of receptor tyrosine kinases-related signaling pathways are common in OCCC.

Methods

We employed combination of poly (ADP-ribose) polymerase (PARP) inhibitors (nirapaib) and lenvatinib targeting key kinases in OCCC to reinforce single-inhibitor initiated pathway rewiring in cell lines, OCCC xenografts, patient-derived xenograft (PDX) model, and ex vivo tumor studies. The potential mechanisms were explored by RNA sequencing before and after combination treatment and related pathways of differentially expressed genes analyzed.

Results

The combination of niraparib and lenvatinib exhibited significant synergistic effects against platinum-resistant OCCC cell lines, in OCCC xenografts, and ex vivo tumor studies. Moreover, the combination of the niraparib and lenvatinib enhanced induction of apoptosis and prolonged survival in PDX model (p = 0.0032). RNA sequencing analyses revealed significant enrichment in structural constituent of ribosome (p = 0.00078). Four ribosomal protein expressions (RPS2, RPS5, RPL3 and RPL9) were validated by real-time quantitative PCR. Nucleophosmin (NPM1) expression, which has been implicated in ribosome biogenesis, was found inhibited by niraparib and lenvatinib. Using Kaplan-Meier plotter database (https://kmplot.com/analysis/) of 1435 ovarian cancer patients, increased NPM1 mRNA expression portended a poor overall survival (p = 0.0025). Our findings taken together imply that combination of niraparib and lenvatinib reduces OCCC progression via attenuation Src phosphorylation, NPM1 expression, and ribosomal biogenesis in OCCC.

Conclusions

Our study supports exploring combination of niraparib and lenvatinib in the treatment of platinum-resistant OCCC.

Clinical trial identification

NA

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

This study was financially supported by grants from the National Science and Technology Council (NSTC 111-2314-B-182A-088) and the Chang Gung Medical Research Foundation (CRRPG3L0011 and CMRPG3M0761).

Disclosure

C. Lai: Financial Interests, Personal and Institutional, Principal Investigator: MSD; Financial Interests, Personal, Advisory Board: Novartis. A. Chao: Financial Interests, Personal and Institutional, Principal Investigator: Seagen Inc., AZ. All other authors have declared no conflicts of interest.