dc.contributor.author | Pancholi, S | |
dc.contributor.author | Ribas, R | |
dc.contributor.author | Simigdala, N | |
dc.contributor.author | Schuster, E | |
dc.contributor.author | Nikitorowicz-Buniak, J | |
dc.contributor.author | Ressa, A | |
dc.contributor.author | Gao, Q | |
dc.contributor.author | Leal, MF | |
dc.contributor.author | Bhamra, A | |
dc.contributor.author | Thornhill, A | |
dc.contributor.author | Morisset, L | |
dc.contributor.author | Montaudon, E | |
dc.contributor.author | Sourd, L | |
dc.contributor.author | Fitzpatrick, M | |
dc.contributor.author | Altelaar, M | |
dc.contributor.author | Johnston, SR | |
dc.contributor.author | Marangoni, E | |
dc.contributor.author | Dowsett, M | |
dc.contributor.author | Martin, L-A | |
dc.date.accessioned | 2020-04-23T09:40:59Z | |
dc.date.issued | 2020-06-18 | |
dc.identifier.citation | Oncogene, 2020, 39 (25), pp. 4781 - 4797 | |
dc.identifier.issn | 0950-9232 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/3597 | |
dc.identifier.eissn | 1476-5594 | |
dc.identifier.doi | 10.1038/s41388-020-1284-6 | |
dc.description.abstract | Combination of CDK4/6 inhibitors and endocrine therapy improves clinical outcome in advanced oestrogen receptor (ER)-positive breast cancer, however relapse is inevitable. Here, we show in model systems that other than loss of RB1 few gene-copy number (CN) alterations are associated with irreversible-resistance to endocrine therapy and subsequent secondary resistance to palbociclib. Resistance to palbociclib occurred as a result of tumour cell re-wiring leading to increased expression of EGFR, MAPK, CDK4, CDK2, CDK7, CCNE1 and CCNE2. Resistance altered the ER genome wide-binding pattern, leading to decreased expression of 'classical' oestrogen-regulated genes and was accompanied by reduced sensitivity to fulvestrant and tamoxifen. Persistent CDK4 blockade decreased phosphorylation of tuberous sclerosis complex 2 (TSC2) enhancing EGFR signalling, leading to the re-wiring of ER. Kinome-knockdown confirmed dependency on ERBB-signalling and G2/M-checkpoint proteins such as WEE1, together with the cell cycle master regulator, CDK7. Noteworthy, sensitivity to CDK7 inhibition was associated with loss of ER and RB1 CN. Overall, we show that resistance to CDK4/6 inhibitors is dependent on kinase re-wiring and the redeployment of signalling cascades previously associated with endocrine resistance and highlights new therapeutic networks that can be exploited upon relapse after CDK4/6 inhibition. | |
dc.format | Print-Electronic | |
dc.format.extent | 4781 - 4797 | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | SPRINGERNATURE | |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0 | |
dc.subject | Cell Line, Tumor | |
dc.subject | Animals | |
dc.subject | Mice, Inbred BALB C | |
dc.subject | Humans | |
dc.subject | Mice, Nude | |
dc.subject | Breast Neoplasms | |
dc.subject | Tamoxifen | |
dc.subject | Piperazines | |
dc.subject | Pyridines | |
dc.subject | Retinoblastoma Protein | |
dc.subject | Receptors, Estrogen | |
dc.subject | Antineoplastic Combined Chemotherapy Protocols | |
dc.subject | Protein Kinase Inhibitors | |
dc.subject | Xenograft Model Antitumor Assays | |
dc.subject | RNA Interference | |
dc.subject | Drug Resistance, Neoplasm | |
dc.subject | Female | |
dc.subject | Cyclin-Dependent Kinase 4 | |
dc.subject | Cyclin-Dependent Kinase 6 | |
dc.subject | MCF-7 Cells | |
dc.subject | Fulvestrant | |
dc.title | Tumour kinome re-wiring governs resistance to palbociclib in oestrogen receptor positive breast cancers, highlighting new therapeutic modalities. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2020-03-24 | |
rioxxterms.versionofrecord | 10.1038/s41388-020-1284-6 | |
rioxxterms.licenseref.uri | https://creativecommons.org/licenses/by/4.0 | |
rioxxterms.licenseref.startdate | 2020-06 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | Oncogene | |
pubs.issue | 25 | |
pubs.notes | No embargo | |
pubs.organisational-group | /ICR | |
pubs.organisational-group | /ICR/Primary Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Breast Cancer Research | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Breast Cancer Research/Endocrine Therapy Resistance | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Breast Cancer Research/Endocrinology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology/Endocrinology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology/Endocrinology/Endocrinology (hon.) | |
pubs.organisational-group | /ICR | |
pubs.organisational-group | /ICR/Primary Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Breast Cancer Research | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Breast Cancer Research/Endocrine Therapy Resistance | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Breast Cancer Research/Endocrinology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology/Endocrinology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology/Endocrinology/Endocrinology (hon.) | |
pubs.publication-status | Published | |
pubs.volume | 39 | |
pubs.embargo.terms | No embargo | |
icr.researchteam | Endocrine Therapy Resistance | |
icr.researchteam | Endocrinology | |
dc.contributor.icrauthor | Pancholi, Sunil | |
dc.contributor.icrauthor | Schuster, Eugene | |
dc.contributor.icrauthor | Gao, Qiong | |