Synergistic combination of cytotoxic chemotherapy and cyclin-dependent kinase 4/6 inhibitors in biliary tract cancers.

التفاصيل البيبلوغرافية
العنوان:	Synergistic combination of cytotoxic chemotherapy and cyclin-dependent kinase 4/6 inhibitors in biliary tract cancers.
المؤلفون:	Arora M; Division of Hematology/Oncology, Department of Internal Medicine, Mayo Clinic, Scottsdale, Arizona, USA.; Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota, USA.; Mayo Clinic Cancer Center, Mayo Clinic, Phoenix, Arizona, USA., Bogenberger JM; Division of Hematology/Oncology, Department of Internal Medicine, Mayo Clinic, Scottsdale, Arizona, USA., Abdelrahman AM; Department of Surgery, Mayo Clinic, Rochester, Minnesota, USA., Yonkus J; Department of Surgery, Mayo Clinic, Rochester, Minnesota, USA., Alva-Ruiz R; Department of Surgery, Mayo Clinic, Rochester, Minnesota, USA., Leiting JL; Department of Surgery, Mayo Clinic, Rochester, Minnesota, USA., Chen X; Department of Informatics, Mayo Clinic, Scottsdale, Arizona, USA., Serrano Uson Junior PL; Division of Hematology/Oncology, Department of Internal Medicine, Mayo Clinic, Scottsdale, Arizona, USA., Dumbauld CR; Division of Hematology/Oncology, Department of Internal Medicine, Mayo Clinic, Scottsdale, Arizona, USA., Baker AT; Division of Hematology/Oncology, Department of Internal Medicine, Mayo Clinic, Scottsdale, Arizona, USA.; Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota, USA.; Mayo Clinic Cancer Center, Mayo Clinic, Phoenix, Arizona, USA.; Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA., Gamb SI; Microscopy and Cell Analysis Core, Mayo Clinic, Rochester, Minnesota, USA., Egan JB; Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota, USA., Zhou Y; Division of Hematology/Oncology, Department of Internal Medicine, Mayo Clinic, Scottsdale, Arizona, USA.; Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota, USA.; Mayo Clinic Cancer Center, Mayo Clinic, Phoenix, Arizona, USA.; Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA., Nagalo BM; Division of Hematology/Oncology, Department of Internal Medicine, Mayo Clinic, Scottsdale, Arizona, USA.; Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota, USA.; Mayo Clinic Cancer Center, Mayo Clinic, Phoenix, Arizona, USA.; Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA., Meurice N; Division of Hematology/Oncology, Department of Internal Medicine, Mayo Clinic, Scottsdale, Arizona, USA.; Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota, USA.; Mayo Clinic Cancer Center, Mayo Clinic, Phoenix, Arizona, USA., Eskelinen EL; Institute of Biomedicine, University of Turku, Turku, Finland., Salomao MA; Department of Laboratory Medicine and Pathology, Mayo Clinic, Scottsdale, Arizona, USA., Kosiorek HE; Department of Health Sciences Research, Mayo Clinic, Scottsdale, Arizona, USA., Braggio E; Division of Hematology/Oncology, Department of Internal Medicine, Mayo Clinic, Scottsdale, Arizona, USA., Barrett MT; Division of Hematology/Oncology, Department of Internal Medicine, Mayo Clinic, Scottsdale, Arizona, USA.; Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota, USA.; Mayo Clinic Cancer Center, Mayo Clinic, Phoenix, Arizona, USA., Buetow KH; Division of Hematology/Oncology, Department of Internal Medicine, Mayo Clinic, Scottsdale, Arizona, USA., Sonbol MB; Division of Hematology/Oncology, Department of Internal Medicine, Mayo Clinic, Scottsdale, Arizona, USA., Mansfield AS; Division of Medical Oncology, Mayo Clinic, Rochester, Minnesota, USA., Roberts LR; Department of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA., Bekaii-Saab TS; Division of Hematology/Oncology, Department of Internal Medicine, Mayo Clinic, Scottsdale, Arizona, USA.; Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota, USA.; Mayo Clinic Cancer Center, Mayo Clinic, Phoenix, Arizona, USA., Ahn DH; Division of Hematology/Oncology, Department of Internal Medicine, Mayo Clinic, Scottsdale, Arizona, USA.; Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota, USA.; Mayo Clinic Cancer Center, Mayo Clinic, Phoenix, Arizona, USA., Truty MJ; Department of Surgery, Mayo Clinic, Rochester, Minnesota, USA., Borad MJ; Division of Hematology/Oncology, Department of Internal Medicine, Mayo Clinic, Scottsdale, Arizona, USA.; Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota, USA.; Mayo Clinic Cancer Center, Mayo Clinic, Phoenix, Arizona, USA.; Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA.
المصدر:	Hepatology (Baltimore, Md.) [Hepatology] 2022 Jan; Vol. 75 (1), pp. 43-58. Date of Electronic Publication: 2021 Dec 12.
نوع المنشور:	Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
اللغة:	English
بيانات الدورية:	Publisher: Wolters Kluwer Health, Inc Country of Publication: United States NLM ID: 8302946 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1527-3350 (Electronic) Linking ISSN: 02709139 NLM ISO Abbreviation: Hepatology Subsets: MEDLINE
أسماء مطبوعة:	Publication: 2023- : [Philadelphia] : Wolters Kluwer Health, Inc. Original Publication: Baltimore, MD : Williams & Wilkins, [c1981]-
مواضيع طبية MeSH:	Antineoplastic Combined Chemotherapy Protocols/pharmacology , Biliary Tract Neoplasms/drug therapy , Protein Kinase Inhibitors/*pharmacology, Animals ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; Autophagy/drug effects ; Biliary Tract Neoplasms/mortality ; Biliary Tract Neoplasms/pathology ; Cisplatin/pharmacology ; Cisplatin/therapeutic use ; Cyclin-Dependent Kinase 4/antagonists & inhibitors ; Cyclin-Dependent Kinase 6/antagonists & inhibitors ; Deoxycytidine/analogs & derivatives ; Deoxycytidine/pharmacology ; Deoxycytidine/therapeutic use ; Drug Synergism ; Humans ; Mice ; Protein Kinase Inhibitors/therapeutic use ; Xenograft Model Antitumor Assays ; Gemcitabine
مستخلص:	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. (© 2021 by the American Association for the Study of Liver Diseases.)
References:	de Groen PC, Gores GJ, LaRusso NF, Gunderson LL, Nagorney DM. Biliary tract cancers. N Engl J Med. 1999;341:1368-78. Valle J, Wasan H, Palmer DH, Cunningham D, Anthoney A, Maraveyas A, et al. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med. 2010;362:1273-81. Eckel F, Schmid RM. Chemotherapy in advanced biliary tract carcinoma: a pooled analysis of clinical trials. Br J Cancer. 2007;96:896-902. Van Dyke AL, Shiels MS, Jones GS, Pfeiffer RM, Petrick JL, Beebe-Dimmer JL, et al. Biliary tract cancer incidence and trends in the United States by demographic group, 1999-2013. Cancer. 2019;125:1489-98. Bogenberger JM, DeLeon TT, Arora M, Ahn DH, Borad MJ. Emerging role of precision medicine in biliary tract cancers. NPJ Precis Oncol. 2018;2:21. Banales JM, Marin JJG, Lamarca A, Rodrigues PM, Khan SA, Roberts LR, et al. Cholangiocarcinoma 2020: the next horizon in mechanisms and management. Nat Rev Gastroenterol Hepatol. 2020;17:557-88. Kang YK, Kim WH, Jang JJ. Expression of G1-S modulators (p53, p16, p27, cyclin D1, Rb) and Smad4/Dpc4 in intrahepatic cholangiocarcinoma. Hum Pathol. 2002;33:877-83. Ahn DH, Javle M, Ahn CW, Jain A, Mikhail S, Noonan AM, et al. Next generation sequencing survey of biliary tract cancer (BTC) reveals the association between tumor somatic variants and chemotherapy resistance. Cancer. 2016;122:3657-66. Zhang J, Su G, Lin Y, Meng W, Lai JKL, Qiao L, et al. Targeting cyclin-dependent kinases in gastrointestinal cancer therapy. Discov Med. 2019;27:27-36. Geoerger B, Bourdeaut F, DuBois SG, Fischer M, Geller JI, Gottardo NG, et al. A phase I study of the CDK4/6 inhibitor ribociclib (LEE011) in pediatric patients with malignant rhabdoid tumors, neuroblastoma, and other solid tumors. Clin Cancer Res. 2017;23:2433-41. Du Q, Guo X, Wang M, Li Y, Sun X, Li Q. The application and prospect of CDK4/6 inhibitors in malignant solid tumors. J Hematol Oncol. 2020;13:41. Torres-Guzmán R, Calsina B, Hermoso A, Baquero C, Alvarez B, Amat J, et al. Preclinical characterization of abemaciclib in hormone receptor positive breast cancer. Oncotarget. 2017;8:69493-507. Al Baghdadi T, Halabi S, Garrett-Mayer E, Mangat PK, Ahn ER, Sahai V, et al. Palbociclib in patients with pancreatic and biliary cancer with CDKN2A alterations: results from the Targeted Agent and Profiling Utilization Registry Study. JCO Precision Oncol. 2019 Aug 14. https://doi.org/10.1200/PO.19.00124. [Epub ahead of print]. Schettini F, De Santo I, Rea CG, De Placido P, Formisano L, Giuliano M, et al. CDK 4/6 inhibitors as single agent in advanced solid tumors. Front Oncol. 2018;8:608. Barroso-Sousa R, Shapiro GI, Tolaney SM. Clinical development of the CDK4/6 inhibitors ribociclib and abemaciclib in breast cancer. Breast Care (Basel). 2016;11:167-73. Patnaik A, Rosen LS, Tolaney SM, Tolcher AW, Goldman JW, Gandhi L, et al. Efficacy and safety of abemaciclib, an inhibitor of CDK4 and CDK6, for patients with breast cancer, non-small cell lung cancer, and other solid tumors. Cancer Discov. 2016;6:740-53. Chong QY, Kok ZH, Bui NLC, Xiang X, Wong AA, Yong WP, et al. A unique CDK4/6 inhibitor: current and future therapeutic strategies of abemaciclib. Pharmacol Res. 2020;156:104686. Teh JLF, Aplin AE. Arrested developments: CDK4/6 inhibitor resistance and alterations in the tumor immune microenvironment. Clin Cancer Res. 2019;25:921-7. Herrera-Abreu MT, Palafox M, Asghar U, Rivas MA, Cutts RJ, Garcia-Murillas I, et al. Early adaptation and acquired resistance to CDK4/6 inhibition in estrogen receptor-positive breast cancer. Cancer Res. 2016;76:2301-13. Capparelli C, Chiavarina B, Whitaker-Menezes D, Pestell TG, Pestell RG, Hulit J, et al. CDK inhibitors (p16/p19/p21) induce senescence and autophagy in cancer-associated fibroblasts, “fueling” tumor growth via paracrine interactions, without an increase in neo-angiogenesis. Cell Cycle. 2012;11:3599-610. Vijayaraghavan S, Karakas C, Doostan I, Chen X, Bui T, Yi M, et al. CDK4/6 and autophagy inhibitors synergistically induce senescence in Rb positive cytoplasmic cyclin E negative cancers. Nat Commun. 2017;8:15916. Kimmelman AC, White E. Autophagy and tumor metabolism. Cell Metab. 2017;25:1037-43. Li YJ, Lei YH, Yao N, Wang CR, Hu N, Ye WC, et al. Autophagy and multidrug resistance in cancer. Chin J Cancer. 2017;36:52. Desantis V, Saltarella I, Lamanuzzi A, Mariggiò MA, Racanelli V, Vacca A, et al. Autophagy: a new mechanism of prosurvival and drug resistance in multiple myeloma. Transl Oncol. 2018;11:1350-7. Franco J, Witkiewicz AK, Knudsen ES. CDK4/6 inhibitors have potent activity in combination with pathway selective therapeutic agents in models of pancreatic cancer. Oncotarget. 2014;5:6512-25. Bar J, Gorn-Hondermann I, Moretto P, Perkins TJ, Niknejad N, Stewart DJ, et al. miR profiling identifies cyclin-dependent kinase 6 downregulation as a potential mechanism of acquired cisplatin resistance in non-small-cell lung carcinoma. Clin Lung Cancer. 2015;16:e121-9. Konecny GE, Winterhoff B, Kolarova T, Qi J, Manivong K, Dering J, et al. Expression of p16 and retinoblastoma determines response to CDK4/6 inhibition in ovarian cancer. Clin Cancer Res. 2011;17:1591-602. Dean JL, McClendon AK, Knudsen ES. Modification of the DNA damage response by therapeutic CDK4/6 inhibition. J Biol Chem. 2012;287:29075-87. McClendon AK, Dean JL, Rivadeneira DB, Yu JE, Reed CA, Gao E, et al. CDK4/6 inhibition antagonizes the cytotoxic response to anthracycline therapy. Cell Cycle. 2012;11:2747-55. Cretella D, Fumarola C, Bonelli M, Alfieri R, La Monica S, Digiacomo G, et al. Pre-treatment with the CDK4/6 inhibitor palbociclib improves the efficacy of paclitaxel in TNBC cells. Sci Rep. 2019;9:13014. Iyengar M, O’Hayer P, Cole A, Sebastian T, Yang K, Coffman L, et al. CDK4/6 inhibition as maintenance and combination therapy for high grade serous ovarian cancer. Oncotarget. 2018;9:15658-72. Gao Y, Shen J, Choy E, Mankin H, Hornicek F, Duan Z. Inhibition of CDK4 sensitizes multidrug resistant ovarian cancer cells to paclitaxel by increasing apoptosiss. Cell Oncol (Dordr). 2017;40:209-18. Gelbert LM, Cai S, Lin XI, Sanchez-Martinez C, del Prado M, Lallena MJ, et al. Preclinical characterization of the CDK4/6 inhibitor LY2835219: in-vivo cell cycle-dependent/independent anti-tumor activities alone/in combination with gemcitabine. Invest New Drugs. 2014;32:825-37. Cao J, Zhu Z, Wang H, Nichols TC, Lui GYL, Deng S, et al. Combining CDK4/6 inhibition with taxanes enhances anti-tumor efficacy by sustained impairment of pRB-E2F pathways in squamous cell lung cancer. Oncogene. 2019;38:4125-41. Weiss JM, Csoszi T, Maglakelidze M, Hoyer RJ, Beck JT, Domine Gomez M, et al. Myelopreservation with the CDK4/6 inhibitor trilaciclib in patients with small-cell lung cancer receiving first-line chemotherapy: a phase Ib/randomized phase II trial. Ann Oncol. 2019;30:1613-21. Tan AR, Wright GS, Thummala AR, Danso MA, Popovic L, Pluard TJ, et al. Trilaciclib plus chemotherapy versus chemotherapy alone in patients with metastatic triple-negative breast cancer: a multicentre, randomised, open-label, phase 2 trial. Lancet Oncol. 2019;20:1587-601. O’Brien N, Conklin D, Beckmann R, Luo T, Chau K, Thomas J, et al. Preclinical activity of abemaciclib alone or in combination with antimitotic and targeted therapies in breast cancer. Mol Cancer Ther. 2018;17:897-907. Chou A, Froio D, Nagrial AM, Parkin A, Murphy KJ, Chin VT, et al. Tailored first-line and second-line CDK4-targeting treatment combinations in mouse models of pancreatic cancer. Gut. 2018;67:2142-55. Kumarasamy V, Ruiz A, Nambiar R, Witkiewicz AK, Erik S, Knudsen ES. Chemotherapy impacts on the cellular response to CDK4/6 inhibition: distinct mechanisms of interaction and efficacy in models of pancreatic cancer. Oncogene. 2020;39:1831-45. Salvador-Barbero B, Álvarez-Fernández M, Zapatero-Solana E, El Bakkali A, Menéndez MDC, López-Casas PP, et al. CDK4/6 inhibitors impair recovery from cytotoxic chemotherapy in pancreatic adenocarcinoma. Cancer Cell. 2020;37:340-53.e6. Roberts PJ, Kumarasamy V, Witkiewicz AK, Erik S, Knudsen ES. Chemotherapy and CDK4/6 inhibitors: unexpected bedfellows. Mol Cancer Ther. 2020;19:1575-88. Arora M, Bogenberger JM, Abdelrahman A, Leiting JL, Chen X, Egan JB, et al. Evaluation of NUC-1031: a first-in-class ProTide in biliary tract cancer. Cancer Chemother Pharmacol. 2020;85:1063-78. Ross JS, Wang K, Javle MM, Catenacci DVT, Shroff RT, Ali SM, et al. Comprehensive genomic profiling of biliary tract cancers to reveal tumor-specific differences and frequency of clinically relevant genomic alterations. J Clin Oncol. 2015;33:4009. Marra A, Curigliano G. Are all cyclin-dependent kinases 4/6 inhibitors created equal? NPJ Breast Cancer. 2019;5:27. Yang C, Li Z, Bhatt T, Dickler M, Giri D, Scaltriti M, et al. Acquired CDK6 amplification promotes breast cancer resistance to CDK4/6 inhibitors and loss of ER signaling and dependence. Oncogene. 2017;36:2255-64. Sun X, Kaufman PD. Ki-67: more than a proliferation marker. Chromosoma. 2018;127:175-86. Engel NW, Schliffke S, Schüller U, Frenzel C, Bokemeyer C, Kubisch C, et al. Fatal myelotoxicity following palliative chemotherapy with cisplatin and gemcitabine in a patient with stage IV cholangiocarcinoma linked to post mortem diagnosis of Fanconi anemia. Front Oncol. 2019 May 22. https://doi.org/10.3389/fonc.2019.00420. [Epub ahead of print]. Song X, Liu X, Wang H, Wang J, Qiao YU, Cigliano A, et al. Combined CDK4/6 and Pan-mTOR inhibition is synergistic against intrahepatic cholangiocarcinoma. Clin Cancer Res. 2019;25:403-13. Chittaranjan S, Bortnik S, Dragowska WH, Xu J, Abeysundara N, Leung A, et al. Autophagy inhibition augments the anticancer effects of epirubicin treatment in anthracycline-sensitive and -resistant triple-negative breast cancer. Clin Cancer Res. 2014;20:3159-73. Lefort S, Joffre C, Kieffer Y, Givel AM, Bourachot B, Zago G, et al. Inhibition of autophagy as a new means of improving chemotherapy efficiency in high-LC3B triple-negative breast cancers. Autophagy. 2014;10:2122-42.
معلومات مُعتمدة:	DP2 CA195764 United States CA NCI NIH HHS; K12 CA090628 United States CA NCI NIH HHS; P50 CA210964 United States CA NCI NIH HHS; K01 CA234324 United States CA NCI NIH HHS
المشرفين على المادة:	0 (Protein Kinase Inhibitors) 0W860991D6 (Deoxycytidine) EC 2.7.11.22 (CDK4 protein, human) EC 2.7.11.22 (CDK6 protein, human) EC 2.7.11.22 (Cyclin-Dependent Kinase 4) EC 2.7.11.22 (Cyclin-Dependent Kinase 6) Q20Q21Q62J (Cisplatin) 0 (Gemcitabine)
تواريخ الأحداث:	Date Created: 20210818 Date Completed: 20220114 Latest Revision: 20221207
رمز التحديث:	20221213
DOI:	10.1002/hep.32102
PMID:	34407567
قاعدة البيانات:	MEDLINE

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تدمد:	1527-3350
DOI:	10.1002/hep.32102