Inibizione di CDK 12 e CDK13 in organoidi di carcinoma ovarico sieroso di alto grado: nuove prospettive terapeutiche

Introduction. High grade serous ovarian cancer (HGSOC) represents the leading cause of death among gynaecological malignancies. Despite all recent therapeutic advances, the median survival of ovarian cancer is about 40-50% at 10 years. Therefore, the identification of more effective chemotherapy regimens and/or target therapies are needed to improve the prognosis of HGSOC patients. Recent studies have shown how patient-derived organoids (PDOs) are powerful tools in molecular oncology, as they can be exploited to bridge the gap between ex-vivo studies and patients' real clinical response to treatments. In this study, by using HGSOC cell lines and PDOs we evaluated the anticancer activity of CDK12/13 inhibition. Materials and Methods. We have collected tumour samples from six patients with HGSOC and we have performed histological, immunohistochemistry and DNA examination. From the same samples we have derived PDOs that we have treated with THZ531, Olaparib, Paclitaxel and carboplatin, alone or in combination. After the treatment we have evaluated the effect of the treatment with THZ531 alone or in combination. Results. All PDOs preserved the phenotypic characteristics of the original tumour and were highly sensitive to THZ531 (IC50 < 140nM). This last data confirmed the importance of CDK12/13 in the survivor of HGSOC cells. In all PDOs BRCA1/2 wild type, the concomitant treatment with sub-optimal dosed of THZ531 (IC30, 30-50nM) and Olaparib (1-10µM) synergistically reduced the cellular viability. The concomitant treatment with Paclitaxel and THZ531 significantly improved the effect of paclitaxel on all PDOs tested. Discussion. In our study, we have confirmed the high sensitivity of HGSOC cells to concomitant inhibition of CDK12/13 activity. Combined treatment with THZ531 has significantly improved the efficacy of PARPi. The results obtained with primary PDOs have clearly indicated that inhibition of CDK12/13 activity can be utilized to rescue the sensitivity of HGSOC BRCA1/2 wild type tumours to PARPi. Our study also has demonstrated that THZ531 significantly improve the cytotoxicity of Paclitaxel. THZ531 synergized with Paclitaxel in all PDO lines tested, even if its effect was stronger for the organoids that were intrinsically more sensitive to this drug.