Evaluating targeted therapies in ovarian cancer metabolism: Novel role for pcsk9 and second generation mtor inhibitors

Dafne Jacome Sanz, Juuli Raivola, Hanna Karvonen, Mariliina Arjama, Harlan Barker, Astrid Murumägi, Daniela Ungureanu

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    Abstract

    Background: Dysregulated lipid metabolism is emerging as a hallmark in several malignancies, including ovarian cancer (OC). Specifically, metastatic OC is highly dependent on lipid-rich omentum. We aimed to investigate the therapeutic value of targeting lipid metabolism in OC. For this purpose, we studied the role of PCSK9, a cholesterol-regulating enzyme, in OC cell survival and its downstream signaling. We also investigated the cytotoxic efficacy of a small library of metabolic (n = 11) and mTOR (n = 10) inhibitors using OC cell lines (n = 8) and ex vivo patient-derived cell cultures (PDCs, n = 5) to identify clinically suitable drug vulnerabilities. Targeting PCSK9 expression with siRNA or PCSK9 specific inhibitor (PF-06446846) impaired OC cell survival. In addi-tion, overexpression of PCSK9 induced robust AKT phosphorylation along with increased expression of ERK1/2 and MEK1/2, suggesting a pro-survival role of PCSK9 in OC cells. Moreover, our drug testing revealed marked differences in cytotoxic responses to drugs targeting metabolic pathways of high-grade serous ovarian cancer (HGSOC) and low-grade serous ovarian cancer (LGSOC) PDCs. Our results show that targeting PCSK9 expression could impair OC cell survival, which warrants further investigation to address the dependency of this cancer on lipogenesis and omental metastasis. Moreover, the differences in metabolic gene expression and drug responses of OC PDCs indicate the existence of a metabolic heterogeneity within OC subtypes, which should be further explored for therapeutic improvements.

    Original languageEnglish
    Article number3727
    JournalCancers
    Volume13
    Issue number15
    DOIs
    Publication statusPublished - Jul 2021
    Publication typeA1 Journal article-refereed

    Keywords

    • Drug testing
    • Metabolism
    • MTOR
    • Omentum
    • Ovarian cancers
    • PCSK9
    • Rapalogs

    Publication forum classification

    • Publication forum level 1

    ASJC Scopus subject areas

    • Oncology
    • Cancer Research

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