Dependency of Cholangiocarcinoma on Cyclin D–Dependent Kinase Activity
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...
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| Veröffentlicht in: | Hepatology (Baltimore, Md.) Md.), 2019-11, Vol.70 (5), p.1614-1630 |
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| creator | Sittithumcharee, Gunya Suppramote, Orawan Vaeteewoottacharn, Kulthida Sirisuksakun, Chumphon Jamnongsong, Supawan Laphanuwat, Phatthamon Suntiparpluacha, Monthira Matha, Arriya Chusorn, Porncheera Buraphat, Pongsakorn Kakanaporn, Chumpot Charngkaew, Komgrid Silsirivanit, Atit Korphaisarn, Krittiya Limsrichamrern, Somchai Tripatara, Pinpat Pairojkul, Chawalit Wongkham, Sopit Sampattavanich, Somponnat Okada, Seiji Jirawatnotai, Siwanon |
| description | 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. |
| doi_str_mv | 10.1002/hep.30704 |
| format | Article |
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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.</description><identifier>ISSN: 0270-9139</identifier><identifier>EISSN: 1527-3350</identifier><identifier>DOI: 10.1002/hep.30704</identifier><identifier>PMID: 31077409</identifier><language>eng</language><publisher>United States: Wolters Kluwer Health, Inc</publisher><subject>Bile ; Bile ducts ; Cancer ; Cholangiocarcinoma ; Cyclin D ; Cyclin D1 ; Cyclin-dependent kinase 4 ; Drug resistance ; Drug therapy ; Hepatology ; Kinases ; Retina ; Retinoblastoma ; Retinoblastoma protein ; Senescence ; Therapeutic applications ; Xenografts</subject><ispartof>Hepatology (Baltimore, Md.), 2019-11, Vol.70 (5), p.1614-1630</ispartof><rights>2019 by the American Association for the Study of Liver Diseases.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4194-aeab997a67bef55c9c5485689f9fc0df685bd7ef2becb81a00067a482dc182b23</citedby><cites>FETCH-LOGICAL-c4194-aeab997a67bef55c9c5485689f9fc0df685bd7ef2becb81a00067a482dc182b23</cites><orcidid>0000-0002-8252-3782</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fhep.30704$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fhep.30704$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,780,784,1417,27924,27925,45574,45575</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31077409$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Sittithumcharee, Gunya</creatorcontrib><creatorcontrib>Suppramote, Orawan</creatorcontrib><creatorcontrib>Vaeteewoottacharn, Kulthida</creatorcontrib><creatorcontrib>Sirisuksakun, Chumphon</creatorcontrib><creatorcontrib>Jamnongsong, Supawan</creatorcontrib><creatorcontrib>Laphanuwat, Phatthamon</creatorcontrib><creatorcontrib>Suntiparpluacha, Monthira</creatorcontrib><creatorcontrib>Matha, Arriya</creatorcontrib><creatorcontrib>Chusorn, Porncheera</creatorcontrib><creatorcontrib>Buraphat, Pongsakorn</creatorcontrib><creatorcontrib>Kakanaporn, Chumpot</creatorcontrib><creatorcontrib>Charngkaew, Komgrid</creatorcontrib><creatorcontrib>Silsirivanit, Atit</creatorcontrib><creatorcontrib>Korphaisarn, Krittiya</creatorcontrib><creatorcontrib>Limsrichamrern, Somchai</creatorcontrib><creatorcontrib>Tripatara, Pinpat</creatorcontrib><creatorcontrib>Pairojkul, Chawalit</creatorcontrib><creatorcontrib>Wongkham, Sopit</creatorcontrib><creatorcontrib>Sampattavanich, Somponnat</creatorcontrib><creatorcontrib>Okada, Seiji</creatorcontrib><creatorcontrib>Jirawatnotai, Siwanon</creatorcontrib><title>Dependency of Cholangiocarcinoma on Cyclin D–Dependent Kinase Activity</title><title>Hepatology (Baltimore, Md.)</title><addtitle>Hepatology</addtitle><description>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.</description><subject>Bile</subject><subject>Bile ducts</subject><subject>Cancer</subject><subject>Cholangiocarcinoma</subject><subject>Cyclin D</subject><subject>Cyclin D1</subject><subject>Cyclin-dependent kinase 4</subject><subject>Drug resistance</subject><subject>Drug therapy</subject><subject>Hepatology</subject><subject>Kinases</subject><subject>Retina</subject><subject>Retinoblastoma</subject><subject>Retinoblastoma protein</subject><subject>Senescence</subject><subject>Therapeutic applications</subject><subject>Xenografts</subject><issn>0270-9139</issn><issn>1527-3350</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><recordid>eNp1kDFOwzAYRi0EoqUwcAEUiQWGtL_tJI7HKi0UUQkGmC3HcairNC5xA8rGHbghJyElLQMS07c8PX16CJ1jGGIAMlro9ZACg-AA9XFImE9pCIeoD4SBzzHlPXTi3BIAeEDiY9SjGBgLgPfRbKLXusx0qRrP5l6ysIUsX4xVslKmtCvp2dJLGlWY0pt8fXzu8Y13b0rptDdWG_NmNs0pOspl4fTZbgfo-Wb6lMz8-cPtXTKe-yrAPPCllinnTEYs1XkYKq7CIA6jmOc8V5DlURymGdM5SbVKYyzbzxGTQUwyhWOSEjpAV513XdnXWruNWBmndNHe1rZ2ghCKOUSURi16-Qdd2roq23eCUOAsjAK2FV53lKqsc5XOxboyK1k1AoPY5hVtXvGTt2UvdsY6Xensl9z3bIFRB7ybQjf_m8Rs-tgpvwElxoPl</recordid><startdate>201911</startdate><enddate>201911</enddate><creator>Sittithumcharee, Gunya</creator><creator>Suppramote, Orawan</creator><creator>Vaeteewoottacharn, Kulthida</creator><creator>Sirisuksakun, Chumphon</creator><creator>Jamnongsong, Supawan</creator><creator>Laphanuwat, Phatthamon</creator><creator>Suntiparpluacha, Monthira</creator><creator>Matha, Arriya</creator><creator>Chusorn, Porncheera</creator><creator>Buraphat, Pongsakorn</creator><creator>Kakanaporn, Chumpot</creator><creator>Charngkaew, Komgrid</creator><creator>Silsirivanit, Atit</creator><creator>Korphaisarn, Krittiya</creator><creator>Limsrichamrern, Somchai</creator><creator>Tripatara, Pinpat</creator><creator>Pairojkul, Chawalit</creator><creator>Wongkham, Sopit</creator><creator>Sampattavanich, Somponnat</creator><creator>Okada, Seiji</creator><creator>Jirawatnotai, Siwanon</creator><general>Wolters Kluwer Health, Inc</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7T5</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>H94</scope><scope>K9.</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0002-8252-3782</orcidid></search><sort><creationdate>201911</creationdate><title>Dependency of Cholangiocarcinoma on Cyclin D–Dependent Kinase Activity</title><author>Sittithumcharee, Gunya ; Suppramote, Orawan ; Vaeteewoottacharn, Kulthida ; Sirisuksakun, Chumphon ; Jamnongsong, Supawan ; Laphanuwat, Phatthamon ; Suntiparpluacha, Monthira ; Matha, Arriya ; Chusorn, Porncheera ; Buraphat, Pongsakorn ; Kakanaporn, Chumpot ; Charngkaew, Komgrid ; Silsirivanit, Atit ; Korphaisarn, Krittiya ; Limsrichamrern, Somchai ; Tripatara, Pinpat ; Pairojkul, Chawalit ; Wongkham, Sopit ; Sampattavanich, Somponnat ; Okada, Seiji ; Jirawatnotai, Siwanon</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4194-aeab997a67bef55c9c5485689f9fc0df685bd7ef2becb81a00067a482dc182b23</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Bile</topic><topic>Bile ducts</topic><topic>Cancer</topic><topic>Cholangiocarcinoma</topic><topic>Cyclin D</topic><topic>Cyclin D1</topic><topic>Cyclin-dependent kinase 4</topic><topic>Drug resistance</topic><topic>Drug therapy</topic><topic>Hepatology</topic><topic>Kinases</topic><topic>Retina</topic><topic>Retinoblastoma</topic><topic>Retinoblastoma protein</topic><topic>Senescence</topic><topic>Therapeutic applications</topic><topic>Xenografts</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Sittithumcharee, Gunya</creatorcontrib><creatorcontrib>Suppramote, Orawan</creatorcontrib><creatorcontrib>Vaeteewoottacharn, Kulthida</creatorcontrib><creatorcontrib>Sirisuksakun, Chumphon</creatorcontrib><creatorcontrib>Jamnongsong, Supawan</creatorcontrib><creatorcontrib>Laphanuwat, Phatthamon</creatorcontrib><creatorcontrib>Suntiparpluacha, Monthira</creatorcontrib><creatorcontrib>Matha, Arriya</creatorcontrib><creatorcontrib>Chusorn, Porncheera</creatorcontrib><creatorcontrib>Buraphat, Pongsakorn</creatorcontrib><creatorcontrib>Kakanaporn, Chumpot</creatorcontrib><creatorcontrib>Charngkaew, Komgrid</creatorcontrib><creatorcontrib>Silsirivanit, Atit</creatorcontrib><creatorcontrib>Korphaisarn, Krittiya</creatorcontrib><creatorcontrib>Limsrichamrern, Somchai</creatorcontrib><creatorcontrib>Tripatara, Pinpat</creatorcontrib><creatorcontrib>Pairojkul, Chawalit</creatorcontrib><creatorcontrib>Wongkham, Sopit</creatorcontrib><creatorcontrib>Sampattavanich, Somponnat</creatorcontrib><creatorcontrib>Okada, Seiji</creatorcontrib><creatorcontrib>Jirawatnotai, Siwanon</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>Immunology Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>MEDLINE - Academic</collection><jtitle>Hepatology (Baltimore, Md.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Sittithumcharee, Gunya</au><au>Suppramote, Orawan</au><au>Vaeteewoottacharn, Kulthida</au><au>Sirisuksakun, Chumphon</au><au>Jamnongsong, Supawan</au><au>Laphanuwat, Phatthamon</au><au>Suntiparpluacha, Monthira</au><au>Matha, Arriya</au><au>Chusorn, Porncheera</au><au>Buraphat, Pongsakorn</au><au>Kakanaporn, Chumpot</au><au>Charngkaew, Komgrid</au><au>Silsirivanit, Atit</au><au>Korphaisarn, Krittiya</au><au>Limsrichamrern, Somchai</au><au>Tripatara, Pinpat</au><au>Pairojkul, Chawalit</au><au>Wongkham, Sopit</au><au>Sampattavanich, Somponnat</au><au>Okada, Seiji</au><au>Jirawatnotai, Siwanon</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Dependency of Cholangiocarcinoma on Cyclin D–Dependent Kinase Activity</atitle><jtitle>Hepatology (Baltimore, Md.)</jtitle><addtitle>Hepatology</addtitle><date>2019-11</date><risdate>2019</risdate><volume>70</volume><issue>5</issue><spage>1614</spage><epage>1630</epage><pages>1614-1630</pages><issn>0270-9139</issn><eissn>1527-3350</eissn><abstract>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.</abstract><cop>United States</cop><pub>Wolters Kluwer Health, Inc</pub><pmid>31077409</pmid><doi>10.1002/hep.30704</doi><tpages>16</tpages><orcidid>https://orcid.org/0000-0002-8252-3782</orcidid></addata></record> |
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| source | Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Wiley Online Library All Journals |
| subjects | Bile Bile ducts Cancer Cholangiocarcinoma Cyclin D Cyclin D1 Cyclin-dependent kinase 4 Drug resistance Drug therapy Hepatology Kinases Retina Retinoblastoma Retinoblastoma protein Senescence Therapeutic applications Xenografts |
| title | Dependency of Cholangiocarcinoma on Cyclin D–Dependent Kinase Activity |
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