Abstract
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, triplettherapy 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.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
Author E-mails: Mansi Arora – Arora.Mansi{at}mayo.edu, James M. Bogenberger – bogenberger{at}hotmail.com, Amro M. Abdelrahman - Abdelrahman.Amro{at}mayo.edu, Jennifer Yonkus – Yonkus.Jennifer{at}mayo.edu, Roberto Alva-Ruiz - Alva-Ruiz.Roberto{at}mayo.edu, Jennifer L. Leiting - Leiting.Jennifer{at}mayo.edu, Xianfeng Chen - Chen.Xianfeng{at}mayo.edu, Pedro Luiz Serrano Uson Junior - SerranoUsonJunior.PedroLuiz{at}mayo.edu, Chelsae R. Dumbauld – Dumbauld.Chelsae{at}mayo.edu, Alexander T. Baker – Baker.Alexander{at}mayo.edu, Scott I. Gamb – Gamb.Scott{at}mayo.edu, Jan B. Egan – Egan.Jan{at}mayo.edu, Yumei Zhou – Zhou.Yumei{at}mayo.edu, Bolni Marius Nagalo - Nagalo.Bolni{at}mayo.edu, Nathalie Meurice – Meurice.Nathalie{at}mayo.edu, Eeva-Liisa Eskelinen - eeva-liisa.eskelinen{at}utu.fi, Marcela A. Salomao - Salomao.Marcela{at}mayo.edu, Heidi E. Kosiorek - Kosiorek.Heidi{at}mayo.edu, Esteban Braggio - Braggio.Esteban{at}mayo.edu, Michael T. Barrett - Barrett.Michael{at}mayo.edu, Kenneth Buetow – Buetow.Kenneth{at}mayo.edu, Mohamad B. Sonbol – Sonbol.Mohamad{at}mayo.edu, Aaron S. Mansfield - Mansfield.Aaron{at}mayo.edu, Lewis R. Roberts – Roberts.Lewis{at}mayo.edu, Tanios S. Bekaii-Saab - Bekaii-Saab.Tanios{at}mayo.edu, Daniel H. Ahn – Ahn.Daniel{at}mayo.edu, Mark J. Truty - Truty.Mark{at}mayo.edu, Mitesh J. Borad – Borad.Mitesh{at}mayo.edu
Financial Support, This work was supported by the National Institute of Health (NIH) through a DP2 Award CA195764 (to MJB); National Cancer Institute (NCI) K12 award CA090628 (to MJB), P50 grant CA210964 (to MJB) and K01 award CA234324 (to BMN); and Mayo Clinic Center for Individualized Medicine (CIM) Precision Cancer Therapeutics Program; and Mayo Clinic Cancer Center. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH.
- Abbreviations
- BTC
- biliary tract cancer;
- SOC
- standard of care;
- CCA
- cholangiocarcinoma;
- GP
- gemcitabine and cisplatin;
- ORR
- overall response rate;
- CDK
- cyclin dependent kinase;
- CDKN2A
- CDK inhibitor 2a;
- RB
- retinoblastoma;
- HR
- hormone receptor;
- MBC
- metastatic breast cancer;
- PDAC
- pancreatic ductal adenocarcinoma;
- TNBC
- triple-negative breast cancer;
- NSCLC
- non-small cell lung cancer;
- RRM1
- ribonucleotide reductase catalytic subunit M1;
- DDR
- drug dose response;
- IC50
- half-maximal inhibitory concentration;
- CI
- combination index;
- PI
- propidium iodide;
- aCGH
- array comparative genomic hybridization;
- NOD
- non-obese diabetic;
- PDX
- patient derived xenograft;
- IP
- intraperitoneal;
- IHC
- immunohistochemistry;
- H&E
- hematoxylin and eosin stain;
- TUNEL
- terminal deoxynucleotide transferase dUTP nick-end labeling;
- R2
- linear regression.