PO-493 Targeting the drug resistance epigenetic driver SMYD3 as a new strategy to potentiate chemotherapeutic effects

IntroductionHuman cancers arise from a combination of genetic and epigenetic changes. Epigenetic factors regulate chromatin structure, affecting biological processes and promoting cancer. Drugs that target epigenetic modifiers are a new therapeutic challenge, due to the reversibility of epi-modifications. Indeed, epigenetic drugs might sensitise cancer resistant cells to chemotherapy. The SMYD3 histone methyltransferase has an oncogenic role in several cancer types. It is overexpressed in various cancers and promotes cell proliferation, making it a potential target for drug discovery.Material and methodsWe performed a virtual screening to identify new compounds able to inhibit SMYD3 and then evaluated phenotypic and molecular changes in cells treated with the selected molecule 4- (aminocarbonyl)-N-(4-bromophenyl)−1-piperidineacetamide (BCI-121). Its inhibitory action was assessed by in vitro methylation and surface plasmon resonance assays. To characterise SMYD3 role in cancer response to therapy, we tested potential changes in the sensitivity of cancer cells treated with a combination of BCI-121 and S-phase-specific drugs. Finally, we investigated SMYD3 contribution in DNA repair by evaluating 53 BP1 nuclear foci formation.Results and discussionsWe observed that SMYD3 is overexpressed in several cancer cell lines, with cells expressing high levels of SMYD3 being highly sensitive to its genetic depletion or pharmacological inhibition by BCI-121. BCI-121 reduces proliferation by arresting cancer cell cycle at the S/G2 boundary. Of note, cell cycle plays a key role in chemosensitivity, particularly for drugs displaying targeted cell cycle effects. Our results showed that pre-treatment with BCI-121 significantly increased cytotoxicity of S-phase agents. Breast cancer cells exposed to DNA damaging agents showed increased levels of nuclear SMYD3 following activation of the repair signals, and an accumulation of unrepaired DNA lesions after SMYD3 genetic ablation. We also evaluated the potential of combined treatment with BCI-121 and S-phase drugs in Triple Negative Breast Cancer (TNBC), which does not usually respond to common therapies. TNBC cells overexpressing SMYD3 confirmed the efficacy of the combined treatment.ConclusionNew therapeutic strategies focused on SMYD3 targeting might overcome cancer resistance to existing drugs, thus allowing not only to reduce dose and side effects, but also to treat cancers not usually responding to common therapies.