CDK4 phosphorylation status and a linked gene expression profile predict sensitivity to palbociclib
Abstract Cyclin D‐CDK4/6 are the first CDK complexes to be activated in the G1 phase in response to oncogenic pathways. The specific CDK4/6 inhibitor PD0332991 (palbociclib) was recently approved by the FDA and EMA for treatment of advanced ER‐positive breast tumors. Unfortunately, no reliable predi...
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| Format: | Article |
| Language: | English |
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Springer Nature
2017-05-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.201607084 |
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| author | Eric Raspé Katia Coulonval Jaime M Pita Sabine Paternot Françoise Rothé Laure Twyffels Sylvain Brohée Ligia Craciun Denis Larsimont Véronique Kruys Flavienne Sandras Isabelle Salmon Steven Van Laere Martine Piccart Michail Ignatiadis Christos Sotiriou Pierre P Roger |
| author_facet | Eric Raspé Katia Coulonval Jaime M Pita Sabine Paternot Françoise Rothé Laure Twyffels Sylvain Brohée Ligia Craciun Denis Larsimont Véronique Kruys Flavienne Sandras Isabelle Salmon Steven Van Laere Martine Piccart Michail Ignatiadis Christos Sotiriou Pierre P Roger |
| author_sort | Eric Raspé |
| collection | DOAJ |
| description | Abstract Cyclin D‐CDK4/6 are the first CDK complexes to be activated in the G1 phase in response to oncogenic pathways. The specific CDK4/6 inhibitor PD0332991 (palbociclib) was recently approved by the FDA and EMA for treatment of advanced ER‐positive breast tumors. Unfortunately, no reliable predictive tools are available for identifying potentially responsive or insensitive tumors. We had shown that the activating T172 phosphorylation of CDK4 is the central rate‐limiting event that initiates the cell cycle decision and signals the presence of active CDK4. Here, we report that the profile of post‐translational modification including T172 phosphorylation of CDK4 differs among breast tumors and associates with their subtypes and risk. A gene expression signature faithfully predicted CDK4 modification profiles in tumors and cell lines. Moreover, in breast cancer cell lines, the CDK4 T172 phosphorylation best correlated with sensitivity to PD0332991. This gene expression signature identifies tumors that are unlikely to respond to CDK4/6 inhibitors and could help to select a subset of patients with HER2‐positive and basal‐like tumors for clinical studies on this class of drugs. |
| format | Article |
| id | doaj-art-9b2d45e7df5c4aa580875b12ef3ec949 |
| institution | Kabale University |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2017-05-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-9b2d45e7df5c4aa580875b12ef3ec9492025-08-20T03:43:14ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842017-05-01981052106610.15252/emmm.201607084CDK4 phosphorylation status and a linked gene expression profile predict sensitivity to palbociclibEric Raspé0Katia Coulonval1Jaime M Pita2Sabine Paternot3Françoise Rothé4Laure Twyffels5Sylvain Brohée6Ligia Craciun7Denis Larsimont8Véronique Kruys9Flavienne Sandras10Isabelle Salmon11Steven Van Laere12Martine Piccart13Michail Ignatiadis14Christos Sotiriou15Pierre P Roger16WELBIO and Institute of Interdisciplinary Research (IRIBHM), Campus Erasme, Université Libre de Bruxelles (ULB)WELBIO and Institute of Interdisciplinary Research (IRIBHM), Campus Erasme, Université Libre de Bruxelles (ULB)WELBIO and Institute of Interdisciplinary Research (IRIBHM), Campus Erasme, Université Libre de Bruxelles (ULB)WELBIO and Institute of Interdisciplinary Research (IRIBHM), Campus Erasme, Université Libre de Bruxelles (ULB)ULB‐Cancer Research Center (U‐CRC), Université Libre de BruxellesLaboratoire de Biologie Moléculaire du Gène, Faculté des Sciences, Université libre de Bruxelles (ULB)ULB‐Cancer Research Center (U‐CRC), Université Libre de BruxellesTumor Bank of the Jules Bordet Institute, Université Libre de Bruxelles (ULB)Department of Pathology, Institut Jules Bordet, Université Libre de Bruxelles (ULB)Laboratoire de Biologie Moléculaire du Gène, Faculté des Sciences, Université libre de Bruxelles (ULB)Department of Pathology, Erasme Hospital, Université Libre de Bruxelles (ULB)ULB‐Cancer Research Center (U‐CRC), Université Libre de BruxellesCenter for Oncological Research (CORE), University of AntwerpULB‐Cancer Research Center (U‐CRC), Université Libre de BruxellesULB‐Cancer Research Center (U‐CRC), Université Libre de BruxellesULB‐Cancer Research Center (U‐CRC), Université Libre de BruxellesWELBIO and Institute of Interdisciplinary Research (IRIBHM), Campus Erasme, Université Libre de Bruxelles (ULB)Abstract Cyclin D‐CDK4/6 are the first CDK complexes to be activated in the G1 phase in response to oncogenic pathways. The specific CDK4/6 inhibitor PD0332991 (palbociclib) was recently approved by the FDA and EMA for treatment of advanced ER‐positive breast tumors. Unfortunately, no reliable predictive tools are available for identifying potentially responsive or insensitive tumors. We had shown that the activating T172 phosphorylation of CDK4 is the central rate‐limiting event that initiates the cell cycle decision and signals the presence of active CDK4. Here, we report that the profile of post‐translational modification including T172 phosphorylation of CDK4 differs among breast tumors and associates with their subtypes and risk. A gene expression signature faithfully predicted CDK4 modification profiles in tumors and cell lines. Moreover, in breast cancer cell lines, the CDK4 T172 phosphorylation best correlated with sensitivity to PD0332991. This gene expression signature identifies tumors that are unlikely to respond to CDK4/6 inhibitors and could help to select a subset of patients with HER2‐positive and basal‐like tumors for clinical studies on this class of drugs.https://doi.org/10.15252/emmm.201607084CDK4/6 inhibitorsbreast cancercyclin‐dependent kinase 4PD0332991sensitivity biomarker |
| spellingShingle | Eric Raspé Katia Coulonval Jaime M Pita Sabine Paternot Françoise Rothé Laure Twyffels Sylvain Brohée Ligia Craciun Denis Larsimont Véronique Kruys Flavienne Sandras Isabelle Salmon Steven Van Laere Martine Piccart Michail Ignatiadis Christos Sotiriou Pierre P Roger CDK4 phosphorylation status and a linked gene expression profile predict sensitivity to palbociclib EMBO Molecular Medicine CDK4/6 inhibitors breast cancer cyclin‐dependent kinase 4 PD0332991 sensitivity biomarker |
| title | CDK4 phosphorylation status and a linked gene expression profile predict sensitivity to palbociclib |
| title_full | CDK4 phosphorylation status and a linked gene expression profile predict sensitivity to palbociclib |
| title_fullStr | CDK4 phosphorylation status and a linked gene expression profile predict sensitivity to palbociclib |
| title_full_unstemmed | CDK4 phosphorylation status and a linked gene expression profile predict sensitivity to palbociclib |
| title_short | CDK4 phosphorylation status and a linked gene expression profile predict sensitivity to palbociclib |
| title_sort | cdk4 phosphorylation status and a linked gene expression profile predict sensitivity to palbociclib |
| topic | CDK4/6 inhibitors breast cancer cyclin‐dependent kinase 4 PD0332991 sensitivity biomarker |
| url | https://doi.org/10.15252/emmm.201607084 |
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