Dependency of Cholangiocarcinoma on Cyclin D-Dependent Kinase Activity.
Journal
Hepatology (Baltimore, Md.)
ISSN: 1527-3350
Titre abrégé: Hepatology
Pays: United States
ID NLM: 8302946
Informations de publication
Date de publication:
11 2019
11 2019
Historique:
received:
26
11
2018
accepted:
26
04
2019
pubmed:
12
5
2019
medline:
3
7
2020
entrez:
12
5
2019
Statut:
ppublish
Résumé
Cholangiocarcinoma (CCA) is a bile duct cancer with a very poor prognosis. Currently, there is no effective pharmacological treatment available for it. We showed that CCA ubiquitously relies on cyclin-dependent kinases 4 and 6 (CDK4/6) activity to proliferate. Primary CCA tissues express high levels of cyclin D1 and the specific marker of CDK4/6 activity, phospho-RB Ser780. Treatment of a 15-CCA cell line collection by pharmacological CDK4/6 inhibitors leads to reduced numbers of cells in the S-phase and senescence in most of the CCA cell lines. We found that expression of retinoblastoma protein (pRB) is required for activity of the CDK4/6 inhibitor, and that loss of pRB conferred CDK4/6 inhibitor-drug resistance. We also identified that sensitivity of CCA to CDK4/6 inhibition is associated with the activated KRAS signature. Effectiveness of CDK4/6 inhibition for CCA was confirmed in the three-dimensional spheroid-, xenograft-, and patient-derived xenograft models. Last, we identified a list of genes whose expressions can be used to predict response to the CDK4/6 inhibitor. Conclusion: We investigated a ubiquitous dependency of CCA on CDK4/6 activity and the universal response to CDK4/6 inhibition. We propose that the CDK4/6-pRB pathway is a suitable therapeutic target for CCA treatment.
Substances chimiques
Cyclin-Dependent Kinase 4
EC 2.7.11.22
Cyclin-Dependent Kinase 6
EC 2.7.11.22
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1614-1630Subventions
Organisme : Thailand Research Fund
ID : RSA5880038
Pays : International
Organisme : Siriraj Foundation
ID : D003421
Pays : International
Organisme : The Foundation for Cancer Care, Siriraj Hospital
Pays : International
Organisme : Siriraj Research Fund
Pays : International
Informations de copyright
© 2019 by the American Association for the Study of Liver Diseases.
Références
BanalesJM, CardinaleV, CarpinoG, MarzioniM, AndersenJB, InvernizziP, et al. Expert consensus document: cholangiocarcinoma: current knowledge and future perspectives consensus statement from the European Network for the Study of Cholangiocarcinoma (ENS-CCA). Nat Rev Gastroenterol Hepatol2016;13:261-280.
SripaB, PairojkulC. Cholangiocarcinoma: lessons from Thailand. Curr Opin Gastroenterol2008;24:349-356.
RizviS, KhanSA, HallemeierCL, KelleyRK, GoresGJ. Cholangiocarcinoma-evolving concepts and therapeutic strategies. Nat Rev Clin Oncol2018;15:95-111.
JiaoY, PawlikTM, AndersRA, SelaruFM, StreppelMM, LucasDJ, et al. Exome sequencing identifies frequent inactivating mutations in BAP1, ARID1A and PBRM1 in intrahepatic cholangiocarcinomas. Nat Genet2013;45:1470-1473.
Chan-OnW, NairismagiML, OngCK, LimWK, DimaS, PairojkulC, et al. Exome sequencing identifies distinct mutational patterns in liver fluke-related and non-infection-related bile duct cancers. Nat Genet2013;45:1474-1478.
BoradMJ, ChampionMD, EganJB, LiangWS, FonsecaR, BryceAH, et al. Integrated genomic characterization reveals novel, therapeutically relevant drug targets in FGFR and EGFR pathways in sporadic intrahepatic cholangiocarcinoma. PLoS Genet2014;10:e1004135.
OngCK, SubimerbC, PairojkulC, WongkhamS, CutcutacheI, YuW, et al. Exome sequencing of liver fluke-associated cholangiocarcinoma. Nat Genet2012;44:690-693.
JusakulA, CutcutacheI, YongCH, LimJQ, HuangMN, PadmanabhanN, et al. Whole-genome and epigenomic landscapes of etiologically distinct subtypes of cholangiocarcinoma. Cancer Discov2017;7:1116-1135.
NakamuraH, AraiY, TotokiY, ShirotaT, ElzawahryA, KatoM, et al. Genomic spectra of biliary tract cancer. Nat Genet2015;47:1003-1010.
LeeH, WangK, JohnsonA, JonesDM, AliSM, ElvinJA, et al. Comprehensive genomic profiling of extrahepatic cholangiocarcinoma reveals a long tail of therapeutic targets. J Clin Pathol2016;69:403-408.
ZouS, LiJ, ZhouH, FrechC, JiangX, ChuJS, et al. Mutational landscape of intrahepatic cholangiocarcinoma. Nat Commun2014;5:5696.
OttoT, SicinskiP. Cell cycle proteins as promising targets in cancer therapy. Nat Rev Cancer2017;17:93-115.
FinnRS, MartinM, RugoHS, JonesS, ImSA, GelmonK, et al. Palbociclib and letrozole in advanced breast cancer. N Engl J Med2016;375:1925-1936.
HortobagyiGN, StemmerSM, BurrisHA, YapYS, SonkeGS, Paluch-ShimonS, et al. Updated results from MONALEESA-2, a phase III trial of first-line ribociclib plus letrozole versus placebo plus letrozole in hormone receptor-positive, HER2-negative advanced breast cancer. Ann Oncol2018;29:1541-1547.
GoetzMP, ToiM, CamponeM, SohnJ, Paluch-ShimonS, HuoberJ, et al. MONARCH 3: abemaciclib as initial therapy for advanced breast cancer. J Clin Oncol2017;35:3638-3646.
Cook SangarML, GenovesiLA, NakamotoMW, DavisMJ, KnobluaghSE, JiP, et al. Inhibition of CDK4/6 by palbociclib significantly extends survival in medulloblastoma patient-derived xenograft mouse models. Clin Cancer Res2017;23:5802-5813.
IriyamaN, HinoH, MoriyaS, HiramotoM, HattaY, TakeiM, MiyazawaK. The cyclin-dependent kinase 4/6 inhibitor, abemaciclib, exerts dose-dependent cytostatic and cytocidal effects and induces autophagy in multiple myeloma cells. Leuk Lymphoma2018;59:1439-1450.
DicksonMA, SchwartzGK, KeohanML, D'AngeloSP, GounderMM, ChiP, et al. Progression-free survival among patients with well-differentiated or dedifferentiated liposarcoma treated with CDK4 inhibitor palbociclib: a phase 2 clinical trial. JAMA Oncol2016;2:937-940.
RossJS, WangK, GayL, Al-RohilR, RandJV, JonesDM, et al. New routes to targeted therapy of intrahepatic cholangiocarcinomas revealed by next-generation sequencing. Oncologist2014;19:235-242.
ChuriCR, ShroffR, WangY, RashidA, KangHC, WeatherlyJ, et al. Mutation profiling in cholangiocarcinoma: prognostic and therapeutic implications. PLoS One2014;9:e115383.
FarshidfarF, ZhengS, GingrasMC, NewtonY, ShihJ, RobertsonAG, et al. Integrative genomic analysis of cholangiocarcinoma identifies distinct IDH-mutant molecular profiles. Cell Rep2017;18:2780-2794.
JirawatnotaiS, AziyuA, OsmundsonEC, MoonsDS, ZouX, KinemanRD, KiyokawaH. Cdk4 is indispensable for postnatal proliferation of the anterior pituitary. J Biol Chem2004;279:51100-51106.
LaphanuwatP, LikasitwatanakulP, SittithumchareeG, ThaphaengphanA, ChomaneeN, SuppramoteO, et al. Cyclin D1 depletion interferes with oxidative balance and promotes cancer cell senescence. J Cell Sci2018;131:jcs214726.
ChaisaingmongkolJ, BudhuA, DangH, RabibhadanaS, PupacdiB, KwonSM, et al. Common molecular subtypes among Asian hepatocellular carcinoma and cholangiocarcinoma. Cancer Cell2017;32:57-70.e3.
KlierM, AnastasovN, HermannA, MeindlT, AngermeierD, RaffeldM, et al. Specific lentiviral shRNA-mediated knockdown of cyclin D1 in mantle cell lymphoma has minimal effects on cell survival and reveals a regulatory circuit with cyclin D2. Leukemia2008;22:2097-2105.
LukasJ, ParryD, AagaardL, MannDJ, BartkovaJ, StraussM, et al. Retinoblastoma-protein-dependent cell-cycle inhibition by the tumour suppressor p16. Nature1995;375:503-506.
WitkiewiczAK, CoxD, KnudsenES. CDK4/6 inhibition provides a potent adjunct to Her2-targeted therapies in preclinical breast cancer models. Genes Cancer2014;5:261-272.
FinnRS, DeringJ, ConklinD, KalousO, CohenDJ, DesaiAJ, et al. PD 0332991, a selective cyclin D kinase 4/6 inhibitor, preferentially inhibits proliferation of luminal estrogen receptor-positive human breast cancer cell lines in vitro. Breast Cancer Res2009;11:R77.
PuyolM, MartinA, DubusP, MuleroF, PizcuetaP, KhanG, et al. A synthetic lethal interaction between K-Ras oncogenes and Cdk4 unveils a therapeutic strategy for non-small cell lung carcinoma. Cancer Cell2010;18:63-73.
MaoCQ, XiongMH, LiuY, ShenS, DuXJ, YangXZ, et al. Synthetic lethal therapy for KRAS mutant non-small-cell lung carcinoma with nanoparticle-mediated CDK4 siRNA delivery. Mol Ther2014;22:964-973.
SubramanianA, TamayoP, MoothaVK, MukherjeeS, EbertBL, GilletteMA, et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A2005;102:15545-15550.
YuQ, SicinskaE, GengY, AhnstromM, ZagozdzonA, KongY, et al. Requirement for CDK4 kinase function in breast cancer. Cancer Cell2006;9:23-32.
ChongDQ, ZhuAX. The landscape of targeted therapies for cholangiocarcinoma: current status and emerging targets. Oncotarget2016;7:46750-46767.
TannapfelA, BenickeM, KatalinicA, UhlmannD, KockerlingF, HaussJ, WittekindC. Frequency of p16(INK4A) alterations and K-ras mutations in intrahepatic cholangiocarcinoma of the liver. Gut2000;47:721-727.
DeanJL, ThangavelC, McClendonAK, ReedCA, KnudsenES. Therapeutic CDK4/6 inhibition in breast cancer: key mechanisms of response and failure. Oncogene2010;29:4018-4032.
JansenVM, BholaNE, BauerJA, FormisanoL, LeeKM, HutchinsonKE, et al. Kinome-wide RNA interference screen reveals a role for PDK1 in acquired resistance to CDK4/6 inhibition in ER-positive breast cancer. Cancer Res2017;77:2488-2499.
ZhangYX, SicinskaE, CzaplinskiJT, RemillardSP, MossS, WangY, et al. Antiproliferative effects of CDK4/6 inhibition in CDK4-amplified human liposarcoma in vitro and in vivo. Mol Cancer Ther2014;13:2184-2193.
LiuL, MichowskiW, InuzukaH, ShimizuK, NihiraNT, ChickJM, et al. G1 cyclins link proliferation, pluripotency and differentiation of embryonic stem cells. Nat Cell Biol2017;19:177-188.
CardinaleV, RenziA, CarpinoG, TorriceA, BragazziMC, GiulianteF, et al. Profiles of cancer stem cell subpopulations in cholangiocarcinomas. Am J Pathol2015;185:1724-1739.