Premium
Synergistic combination of cytotoxic chemotherapy and cyclin‐dependent kinase 4/6 inhibitors in biliary tract cancers
Author(s) -
Arora Mansi,
Bogenberger James M.,
Abdelrahman Amro M.,
Yonkus Jennifer,
AlvaRuiz Roberto,
Leiting Jennifer L.,
Chen Xianfeng,
Serrano Uson Junior Pedro Luiz,
Dumbauld Chelsae R.,
Baker Alexander T.,
Gamb Scott I.,
Egan Jan B.,
Zhou Yumei,
Nagalo Bolni Marius,
Meurice Nathalie,
Eskelinen EevaLiisa,
Salomao Marcela A.,
Kosiorek Heidi E.,
Braggio Esteban,
Barrett Michael T.,
Buetow Kenneth H.,
Sonbol Mohamad B.,
Mansfield Aaron S.,
Roberts Lewis R.,
BekaiiSaab Tanios S.,
Ahn Daniel H.,
Truty Mark J.,
Borad Mitesh J.
Publication year - 2022
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.32102
Subject(s) - gemcitabine , cisplatin , medicine , combination therapy , pharmacology , chemotherapy , cancer research , cyclin dependent kinase , palbociclib , oncology , cell cycle , cancer , metastatic breast cancer , breast cancer
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.