dc.contributor.author | Fearon, AE | |
dc.contributor.author | Carter, EP | |
dc.contributor.author | Clayton, NS | |
dc.contributor.author | Wilkes, EH | |
dc.contributor.author | Baker, A-M | |
dc.contributor.author | Kapitonova, E | |
dc.contributor.author | Bakhouche, BA | |
dc.contributor.author | Tanner, Y | |
dc.contributor.author | Wang, J | |
dc.contributor.author | Gadaleta, E | |
dc.contributor.author | Chelala, C | |
dc.contributor.author | Moore, KM | |
dc.contributor.author | Marshall, JF | |
dc.contributor.author | Chupin, J | |
dc.contributor.author | Schmid, P | |
dc.contributor.author | Jones, JL | |
dc.contributor.author | Lockley, M | |
dc.contributor.author | Cutillas, PR | |
dc.contributor.author | Grose, RP | |
dc.date.accessioned | 2019-03-22T11:26:52Z | |
dc.date.available | 2018-02-06 | |
dc.date.available | 2019-03-22T11:26:52Z | |
dc.date.issued | 2018-02-27 | |
dc.identifier.citation | Fearon, A. E., et al. (2018). "PHLDA1 Mediates Drug Resistance in Receptor Tyrosine Kinase-Driven Cancer." Cell Reports 22(9): 2469-2481. | en_US |
dc.identifier.issn | 2211-1247 | |
dc.identifier.uri | https://qmro.qmul.ac.uk/xmlui/handle/123456789/56422 | |
dc.description.abstract | Development of resistance causes failure of drugs targeting receptor tyrosine kinase (RTK) networks and represents a critical challenge for precision medicine. Here, we show that PHLDA1 downregulation is critical to acquisition and maintenance of drug resistance in RTK-driven cancer. Using fibroblast growth factor receptor (FGFR) inhibition in endometrial cancer cells, we identify an Akt-driven compensatory mechanism underpinned by downregulation of PHLDA1. We demonstrate broad clinical relevance of our findings, showing that PHLDA1 downregulation also occurs in response to RTK-targeted therapy in breast and renal cancer patients, as well as following trastuzumab treatment in HER2+ breast cancer cells. Crucially, knockdown of PHLDA1 alone was sufficient to confer de novo resistance to RTK inhibitors and induction of PHLDA1 expression re-sensitized drug-resistant cancer cells to targeted therapies, identifying PHLDA1 as a biomarker for drug response and highlighting the potential of PHLDA1 reactivation as a means of circumventing drug resistance. | en_US |
dc.description.sponsorship | This work was supported by Cancer Research UK (C16420/A12995), the Barry Reed Research Fund (576/2334 SPF1001), Breast Cancer Now (2012 November PR052), the CRUK/DH Barts Experimental Cancer Medicine Centre (C16420/A15583), and by a Cancer Research UK Centre Grant to Barts Cancer Institute (C16420/A18066). | en_US |
dc.format.extent | 2469 - 2481 | |
dc.language.iso | en | en_US |
dc.publisher | Elsevier/Science Direct | en_US |
dc.relation.ispartof | CELL REPORTS | |
dc.rights | Creative Commons Attribution | |
dc.rights | Attribution 3.0 United States | * |
dc.rights.uri | http://creativecommons.org/licenses/by/3.0/us/ | * |
dc.subject | Drug Resistance | en_US |
dc.subject | Cancer | en_US |
dc.subject | receptor tyrosine kinase networks | en_US |
dc.subject | PHLDA1 | en_US |
dc.title | PHLDA1 Mediates Drug Resistance in Receptor Tyrosine Kinase-Driven Cancer | en_US |
dc.type | Article | en_US |
dc.rights.holder | 2018 The Author(s). | |
dc.identifier.doi | 10.1016/j.celrep.2018.02.028 | |
pubs.author-url | http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000426243000021&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=612ae0d773dcbdba3046f6df545e9f6a | en_US |
pubs.issue | 9 | en_US |
pubs.notes | Not known | en_US |
pubs.publication-status | Published | en_US |
pubs.volume | 22 | en_US |
dcterms.dateAccepted | 2018-02-06 | |
rioxxterms.funder | Default funder | en_US |
rioxxterms.identifier.project | Default project | en_US |
qmul.funder | New treatments for chemotherapy resistant high grader serous ovarian cancer::CRUK | en_US |