Synergistic combination of cytotoxic chemotherapy and cyclin‐dependent kinase 4/6 inhibitors in biliary tract cancers
Year: 2021
Type: article
Abstract: BACKGROUND AND AIMS: Biliary tract cancers (BTCs) are uncommon, but highly lethal, gastrointestinal malignancies. Gemcitabine/cisplatin is a standard-of-care systemic therapy, but has a modest impact on survival and harbors toxicities, including myelosuppression, nephropathy, neuropathy, and ototoxicity. Whereas BTCs are characterized by aberrations activating the cyclinD1/cyclin-dependent kinase (CDK)4/6/CDK inhibitor 2a/retinoblastoma pathway, clinical use of CDK4/6 inhibitors as monotherapy is limited by lack of validated biomarkers, diffident preclinical efficacy, and development of acquired drug resistance. Emerging studies have explored therapeutic strategies to enhance the antitumor efficacy of CDK4/6 inhibitors by the combination with chemotherapy regimens, but their mechanism of action remains elusive. APPROACH AND RESULTS: 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 attributable to autophagy-induced resistance. Notably, triplet therapy was able to potentiate efficacy through elimination of the autophagic flux. Correspondingly, abemaciclib potentiated ribonucleotide reductase catalytic subunit M1 reduction, resulting in sensitization to gemcitabine. CONCLUSIONS: As such, these data provide robust preclinical 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.
Source: Hepatology
DOI: 10.1002/hep.32102
Authors: Mansi Arora, James M. Bogenberger, Amro M. Abdelrahman, Jennifer Yonkus, Roberto Alva‐Ruiz, Jennifer L. Leiting, Xianfeng Chen, Pedro Luiz Serrano Uson Junior, Chelsae R. Dumbauld, Alexander T. Baker, Scott I. Gamb, Jan B. Egan, Yumei Zhou, Bolni Marius Nagalo, Nathalie Meurice, Eeva‐Liisa Eskelinen, Marcela A. Salomao, Heidi E. Kosiorek, Esteban Braggio, Michael T. Barrett, Kenneth H. Buetow, Mohamad B. Sonbol, Aaron S. Mansfield, Lewis R. Roberts, Tanios S. Bekaii‐Saab, Daniel H. Ahn, Mark J. Truty, Mitesh J. Borad
Language: English
Subfield: Surgery
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: G2824535170, G4451258999, G5333760487, cGAS-STING Pathway Targeting Replicative Adenoviruses with CD46 Tropism and AFP Promoter Conditional Replication Restriction for the Treatment of Hepatocellular Carcinoma, G6644448087, Oncolytic Virotherapy in Hepatocellular Cancer, G7114658202, G732393567, G8952271581, G9000066704, Paul Calabresi Program in Clinical/Translational Research at Mayo Clinic
OpenAlex ID: W3193816650