Synergistic Combination of Cytotoxic Chemotherapy and Cyclin Dependent Kinase 4/6 Inhibitors in Biliary Tract Cancers

Biliary tract cancers (BTCs) are uncommon but highly lethal gastrointestinal malignancies. Gemcitabine/cisplatin is a standard-of-care (SOC) systemic therapy, but has a modest impact on survival and harbor toxicities including myelosuppression, nephropathy, neuropathy and ototoxicity. While BTCs are characterized by aberrations activating the cyclinD1-CDK4/6-CDKN2A-RB pathway, clinical use of CDK4/6 inhibitors as monotherapy is limited by lack of validated biomarkers, diffident pre-clinical efficacy and development of acquired drug resistance. Emerging studies have explored therapeutic strategies to enhance the anti-tumor efficacy of CDK4/6 inhibitors by combination with chemotherapy-regimens but their mechanism of action remains elusive. Here, we report in vitro and in vivo synergy in BTC models, showing enhanced efficacy, reduced toxicity and better survival with a combination comprising gemcitabine/cisplatin and CDK4/6 inhibitors. Furthermore, we demonstrated that abemaciclib monotherapy had only modest efficacy due to autophagy induced resistance. Notably, triplet-therapy was able to potentiate efficacy through elimination of the autophagic flux. Correspondingly, abemaciclib potentiated RRM1 reduction, resulting in sensitization to gemcitabine. Conclusions: As such, these data provide robust pre-clinical mechanistic evidence of synergy between gemcitabine/cisplatin and CDK4/6 inhibitors, and delineate a path forward for translation of these findings to preliminary clinical studies in advanced BTC patients.