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Serbian Association for Cancer Research                                                       SDIRSACR


                                                                                                             P11

           Sensitizing hepatocellular carcinoma (HCC) cells to lenvatinib via activation of the ferroptosis pathway:
                                                                                    insight on SECTM1 as a target


                                                               Cyrollah Disoma , Claudio Tiribelli , Caecilia Sukowati 1,3
                                                                              1,2
                                                                                              2
                              1Department of Life Sciences, Doctoral School of Molecular Medicine, University of Trieste, Trieste, Italy
          2Liver Cancer Unit, Fondazione Italiana Fegato ONLUS (Italian Liver Foundation NPO), AREA Science Park Basovizza, Trieste, Italy
            3Eijkman Research Center for Molecular Biology, Research Organization for Health, National Research and Innovation Agency,
                                                                                                  Jakarta, Indonesia

        Keywords: drug resistance, hepatocellular carcinoma, lenvatinib

        Background: The prognosis of hepatocellular carcinoma (HCC) remains poor due to late diagnosis, tumor recurrence,
        and drug resistance. Lenvatinib, an oral multi-kinase inhibitor, was approved for patients with unresectable HCC in
        2018. However, the genetic heterogeneity of HCC tumors is highly associated with primary resistance. Previously, we
        identified novel genes associated with lenvatinib resistance by analyzing four public datasets and validated them in
        HCC cells. In this study, we aimed to determine the molecular mechanism of these genes that enables the cells to be
        sensitive to lenvatinib.
        Materials and Methods: MTT assay was performed in HCC cells treated with ferroptosis activators (erastin and RSL3)
        for 24, 48, and 72 hours. Based on the IC50 values, two doses of the activators were selected for further experiments.
        Huh7 cells were treated with erastin (0.1µm and 1.0µm) and RSL3 (0.01µm and 0.05µm) for 24h. Five lenvatinib
        resistance genes were probed by RT-qPCR in HCC cells and in human tissue samples.
        Results: MTT assay showed that Huh7 cells were more sensitive to ferroptosis activators than JHH6 cells. The different
        drug responses could be due to the inherent differences between the two cell lines, with Huh7 being less aggressive
        with lower metastatic potential and JHH6 cells being highly tumorigenic with greater metastatic potential. In Huh7 cells
        treated with lenvatinib, there was significant upregulation of SECTM1, IFI6, and NPC1L1. In Hep3B cells, all five genes
        (SECTM1, IFI6, NPC1L1, FBLN7 and SEZ6L2) were upregulated. Interestingly, in Huh7 cells treated with ferroptosis
        activators, there was downregulation of SECTM1, FBLN7, and NPC1L1. This suggests that the activation of ferroptosis
        sensitizes cells to lenvatinib, and this event is gene-dependent. Of the five candidate genes, SECTM1 expression was
        analyzed in 61 paired human HCC tissue samples. SECTM1 was significantly upregulated in tumor tissues compared
        with the adjacent normal liver tissue (p=0.001). High SECTM1 expression was associated with poor prognosis with
        overall survival probability of 45% vs 60% in low-expressing patients. There was higher SECTM1 expression in Grade 4
        tumors compared to lower grades and in nodal metastasis.
        Conclusions: The high expression of certain genes is associated with resistance to lenvatinib. Here, we show that
        sensitivity to lenvatinib can be achieved via activation of ferroptosis. Overall, our current study revealed SECTM1 as a
        possible therapeutic target.

        Acknowledgments and funding: Cyrollah Disoma would like to thank the Department of Science and Technology-
        Philippine Council for Health Research and Development (DOST-PCHRD).





                                                                                                             P12

                                                The effect of PDK1 inhibition on human breast cancer cell growth

                   Dimitra Alexopoulou, Κonstantina Stergiou, Fani Koutsougianni, Kostas Lafazanis, Evaggelia Papadogianni,
                                                                                               Konstantinos Dimas

                   Department of Pharmacology, Faculty of Medicine, School of Health Sciences, University of Thessaly, Larissa, Greece.

        Keywords: 3-phosphoinositide-dependent protein kinase 1; cell death; RNA, small interfering; triple negative breast
        neoplasms

        Background: Phosphoinositide-dependent kinase-1 (PDK1) is a major serine/threonine kinase that regulates various
        cellular processes including survival, proliferation, and migration through the PI3K/AKT/mTOR and MAPK/RSK pathways.

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