Publications Repository

Publications Repository

View Item 
  •   Home
  • ICR Divisions
  • Breast Cancer Research
  • View Item
  • Home
  • ICR Divisions
  • Breast Cancer Research
  • View Item
JavaScript is disabled for your browser. Some features of this site may not work without it.

Genetic Alterations in the PI3K/AKT Pathway and Baseline AKT Activity Define AKT Inhibitor Sensitivity in Breast Cancer Patient-derived Xenografts.

Thumbnail
View/Open
Accepted version (3.902Mb)
Publication Date
2020-07
ICR Author
Turner, Nicholas
Bruna Cabot, Alejandra
Author
Gris-Oliver, A
Palafox, M
Monserrat, L
Brasó-Maristany, F
Òdena, A
Sánchez-Guixé, M
Ibrahim, YH
Villacampa, G
Grueso, J
Parés, M
Guzmán, M
Rodríguez, O
Bruna, A
Hirst, CS
Barnicle, A
de Bruin, EC
Reddy, A
Schiavon, G
Arribas, J
Mills, GB
Caldas, C
Dienstmann, R
Prat, A
Nuciforo, P
Razavi, P
Scaltriti, M
Turner, NC
Saura, C
Davies, BR
Oliveira, M
Serra, V
Type
Journal Article
Metadata
Show full item record
Abstract
<h4>Purpose</h4>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.<h4>Experimental design</h4>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.<h4>Results</h4>Four PDX were derived from patients receiving AZD5363 in the clinic which exhibited concordant treatment response. Mutations in <i>PIK3CA</i>/<i>AKT1</i> and absence of mTOR complex 1 (mTORC1)-activating alterations, for example, in <i>MTOR</i> or <i>TSC1</i>, were associated with sensitivity to AZD5363 monotherapy. Interestingly, excluding <i>PTEN</i> 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 <i>AKT1</i> p.E17K.<h4>Conclusions</h4>This study provides insight into putative predictive biomarkers of response and acquired resistance to AZD5363 in HER2-negative metastatic breast cancer.
URL
https://repository.icr.ac.uk/handle/internal/3626
Collections
  • Breast Cancer Research
  • Molecular Pathology
Licenseref URL
http://www.rioxx.net/licenses/under-embargo-all-rights-reserved
Version of record
10.1158/1078-0432.ccr-19-3324
Research team
Molecular Oncology
Preclinical Modelling of Paediatric Cancer Evolution
Language
eng
Date accepted
2020-03-24
License start date
2020-07
Citation
Clinical cancer research : an official journal of the American Association for Cancer Research, 2020, 26 (14), pp. 3720 - 3731

Browse

All of ICR repositoryICR DivisionsIssue dateAuthorsTitlesSubjectsThis collectionIssue dateAuthorsTitlesSubjects

Statistics

Most popular itemsStatistics by countryMost popular authors
  • Login
  • Registered office: The Institute of Cancer Research, 123 Old Brompton Road, London, SW7 3RP
    A Charity, Not for Profit. Company Limited by Guarantee.
    Registered in England No. 534147. VAT Registration No. GB 849 0581 02.