Genetic alterations in the PI3K/AKT pathway and baseline AKT activity define AKT inhibitor sensitivity in breast cancer patient-derived xenografts Journal Article
| Authors: | Gris-Oliver, A.; Palafox, M.; Monserrat, L.; Brasó-Maristany, F.; Òdena, A.; Sánchez-Guixé, M.; Ibrahim, Y. H.; Villacampa, G.; Grueso, J.; Parés, M.; Guzmán, M.; Rodríguez, O.; Bruna, A.; Hirst, C. S.; Barnicle, A.; de Bruin, E. C.; Reddy, A.; Schiavon, G.; Arribas, J.; Mills, G. B.; Caldas, C.; Dienstmann, R.; Prat, A.; Nuciforo, P.; Razavi, P.; Scaltriti, M.; Turner, N. C.; Saura, C.; Davies, B. R.; Oliveira, M.; Serra, V. |
| Article Title: | Genetic alterations in the PI3K/AKT pathway and baseline AKT activity define AKT inhibitor sensitivity in breast cancer patient-derived xenografts |
| 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. ©2020 American Association for Cancer Research. |
| Journal Title: | Clinical Cancer Research |
| Volume: | 26 |
| Issue: | 14 |
| ISSN: | 1078-0432 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2020-07-15 |
| Start Page: | 3720 |
| End Page: | 3731 |
| Language: | English |
| DOI: | 10.1158/1078-0432.Ccr-19-3324 |
| PUBMED: | 32220884 |
| PROVIDER: | scopus |
| PMCID: | PMC7814659 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 3 August 2020 -- Source: Scopus |
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