PO-028 Effectiveness and molecular basis of cdk4/6 inhibition in combination with taxanes in pancreatic cancer

Introduction Pancreatic Ductal Adenocarcinoma (PDAC) is among the deadliest human cancers with a 5 year survival rate of less than 5% using the standard of care gemcitabine/nab-paclitaxel. The most frequently disrupted genes in PDACs are first K-RAS and second CDKN2A, which encodes the cyclin-dependent kinase (CDK)4/6 inhibitor p16. Recently, CDK4/6 inhibitors have been approved for breast cancer treatment, and preclinical assays for PDAC are giving promising results. Material and methods PDAC Patient-Derived Xenografts (PDX) models and PDX-derived cell lines were used for in vivo and in vitro studies, respectively. Cellular studies were performed using proliferation and cell cycle assays in combination with flow cytometry, immunoblotting, fluorescence microscopy and live cell imaging techniques. Drug treatments were performed with the CDK4/6 inhibitor PD-0332991 (Palbociclib), and with Paclitaxel (Taxol) or Nab-Paclitaxel (Abraxane) for in vitro and in vivo studies, respectively. Results and discussions Treatment of different PDX-derived cell lines with the combination of taxanes and CDK4/6 inhibitors resulted in a higher anti-proliferative effect than both drugs used as single agent. Cell cycle studies showed that inhibition of CDK4/6 prevented recovery from treatment with taxol. At the molecular level we found that the combined treatment induced a clear interruption in retinoblastoma pathway, even higher than CDK4/6 inhibition in monotherapy. Gene expression profiles comparing single versus combined treatment are currently being performed to further understand the molecular basis underlying the effectiveness of this type of treatment. Moreover, to assess the efficacy of this new combined treatment in vivo, we treated nine PDAC PDX models with PD-0332991 and nab-paclitaxel, following the same schedule. Importantly, eight of them presented an increased tumour growth inhibition in the combination with respect to the monotherapies. Conclusion Although the molecular mechanism underlying the effectiveness of this treatment is not completely understood yet, our data suggest a good therapeutic value for the combination of CDK4/6 inhibitors and taxanes in PDAC treatment.