dc.contributor.author | Gris-Oliver, A | |
dc.contributor.author | Palafox, M | |
dc.contributor.author | Monserrat, L | |
dc.contributor.author | Brasó-Maristany, F | |
dc.contributor.author | Òdena, A | |
dc.contributor.author | Sánchez-Guixé, M | |
dc.contributor.author | Ibrahim, YH | |
dc.contributor.author | Villacampa, G | |
dc.contributor.author | Grueso, J | |
dc.contributor.author | Parés, M | |
dc.contributor.author | Guzmán, M | |
dc.contributor.author | Rodríguez, O | |
dc.contributor.author | Bruna, A | |
dc.contributor.author | Hirst, CS | |
dc.contributor.author | Barnicle, A | |
dc.contributor.author | de Bruin, EC | |
dc.contributor.author | Reddy, A | |
dc.contributor.author | Schiavon, G | |
dc.contributor.author | Arribas, J | |
dc.contributor.author | Mills, GB | |
dc.contributor.author | Caldas, C | |
dc.contributor.author | Dienstmann, R | |
dc.contributor.author | Prat, A | |
dc.contributor.author | Nuciforo, P | |
dc.contributor.author | Razavi, P | |
dc.contributor.author | Scaltriti, M | |
dc.contributor.author | Turner, NC | |
dc.contributor.author | Saura, C | |
dc.contributor.author | Davies, BR | |
dc.contributor.author | Oliveira, M | |
dc.contributor.author | Serra, V | |
dc.date.accessioned | 2020-05-22T13:58:45Z | |
dc.date.accessioned | 2020-05-22T14:03:05Z | |
dc.date.issued | 2020-07-15 | |
dc.identifier.citation | Clinical cancer research : an official journal of the American Association for Cancer Research, 2020, 26 (14), pp. 3720 - 3731 | |
dc.identifier.issn | 1078-0432 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/3626 | |
dc.identifier.eissn | 1557-3265 | |
dc.identifier.doi | 10.1158/1078-0432.ccr-19-3324 | |
dc.description.abstract | PURPOSE: AZD5363/capivasertib is a pan-AKT catalytic inhibitor with promising activity in combination with paclitaxel in triple-negative metastatic breast cancer harboring PI3K/AKT-pathway alterations and in estrogen receptor-positive breast cancer in combination with fulvestrant. Here, we aimed to identify response biomarkers and uncover mechanisms of resistance to AZD5363 and its combination with paclitaxel. EXPERIMENTAL DESIGN: Genetic and proteomic markers were analyzed in 28 HER2-negative patient-derived xenografts (PDXs) and in patient samples, and correlated to AZD5363 sensitivity as single agent and in combination with paclitaxel. RESULTS: Four PDX were derived from patients receiving AZD5363 in the clinic which exhibited concordant treatment response. Mutations in PIK3CA/AKT1 and absence of mTOR complex 1 (mTORC1)-activating alterations, for example, in MTOR or TSC1, were associated with sensitivity to AZD5363 monotherapy. Interestingly, excluding PTEN from the composite biomarker increased its accuracy from 64% to 89%. Moreover, resistant PDXs exhibited low baseline pAKT S473 and residual pS6 S235 upon treatment, suggesting that parallel pathways bypass AKT/S6K1 signaling in these models. We identified two mechanisms of acquired resistance to AZD5363: cyclin D1 overexpression and loss of AKT1 p.E17K. CONCLUSIONS: This study provides insight into putative predictive biomarkers of response and acquired resistance to AZD5363 in HER2-negative metastatic breast cancer. | |
dc.format | Print-Electronic | |
dc.format.extent | 3720 - 3731 | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | AMER ASSOC CANCER RESEARCH | |
dc.relation.replaces | https://repository.icr.ac.uk/handle/internal/3625 | |
dc.relation.replaces | internal/3625 | |
dc.rights.uri | https://www.rioxx.net/licenses/under-embargo-all-rights-reserved | |
dc.title | Genetic Alterations in the PI3K/AKT Pathway and Baseline AKT Activity Define AKT Inhibitor Sensitivity in Breast Cancer Patient-derived Xenografts. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2020-03-24 | |
rioxxterms.versionofrecord | 10.1158/1078-0432.ccr-19-3324 | |
rioxxterms.licenseref.uri | https://www.rioxx.net/licenses/under-embargo-all-rights-reserved | |
rioxxterms.licenseref.startdate | 2020-07 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | Clinical cancer research : an official journal of the American Association for Cancer Research | |
pubs.issue | 14 | |
pubs.notes | Not known | |
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/Molecular Oncology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology/Preclinical Modelling of Paediatric Cancer Evolution | |
pubs.publication-status | Published | |
pubs.volume | 26 | |
pubs.embargo.terms | Not known | |
icr.researchteam | Molecular Oncology | |
icr.researchteam | Preclinical Modelling of Paediatric Cancer Evolution | |
dc.contributor.icrauthor | Bruna Cabot, Alejandra | |
dc.contributor.icrauthor | Turner, Nicholas | |