Targeting the PI3K/Akt/mTOR pathway with the pan-Akt inhibitor GDC-0068 in PIK3CA-mutant breast cancer brain metastases.

Autor:	Ippen FM; Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.; Department of Neurology, Heidelberg University Hospital, Heidelberg, Germany., Grosch JK; Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.; Department of Neurology, Heidelberg University Hospital, Heidelberg, Germany., Subramanian M; Genentech, Inc, Drug Metabolism and Pharmacokinetics, South San Francisco, California, USA., Kuter BM; Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA., Liederer BM; Genentech, Inc, Drug Metabolism and Pharmacokinetics, South San Francisco, California, USA., Plise EG; Genentech, Inc, Drug Metabolism and Pharmacokinetics, South San Francisco, California, USA., Mora JL; Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA., Nayyar N; Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA., Schmidt SP; Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA., Giobbie-Hurder A; Division of Biostatistics, Department of Data Sciences, Dana-Farber Cancer Institute, Boston, Massachusetts, USA., Martinez-Lage M; Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA., Carter SL; Joint Center for Cancer Precision Medicine, Dana-Farber Cancer Institute/Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA., Cahill DP; Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA., Wakimoto H; Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA., Brastianos PK; Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Jazyk:	angličtina
Zdroj:	Neuro-oncology [Neuro Oncol] 2019 Nov 04; Vol. 21 (11), pp. 1401-1411.
DOI:	10.1093/neuonc/noz105
Abstrakt:	Background: Activating mutations in the pathway of phosphatidylinositol-3 kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) occur in 43-70% of breast cancer brain metastasis patients. To date, the treatment of these patients presents an ongoing challenge, mainly because of the lack of targeted agents that are able to sufficiently penetrate the blood-brain barrier. GDC-0068 is a pan-Akt inhibitor that has shown to be effective in various preclinical tumor models as well as in clinical trials. The purpose of this study was to analyze the efficacy of GDC-0068 in a breast cancer brain metastases model. Methods: In in vitro studies, antitumor activity of GDC-0068 was assessed in breast cancer cells of phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA)-mutant and PIK3CA-wildtype breast cancer cell lines using cell viability and apoptosis assays, cell cycle analysis, and western blots. In vivo, the efficacy of GDC-0068 was analyzed in a PIK3CA-mutant breast cancer brain metastasis orthotopic xenograft mouse model and evaluated by repeated bioluminescent imaging and immunohistochemistry. Results: GDC-0068 decreased cell viability, induced apoptosis, and inhibited phosphorylation of proline rich Akt substrate 40 kDa and p70 S6 kinase in a dose-dependent manner in PIK3CA-mutant breast cancer brain metastatic cell lines compared with PIK3CA-wildtype cell lines. In vivo, treatment with GDC-0068 notably inhibited the growth of PIK3CA-mutant tumors and resulted in a significant survival benefit compared with sham, whereas no effect was detected in a PIK3CA-wildtype model. Conclusions: This study suggests that the Akt inhibitor GDC-0068 may be an encouraging targeted treatment strategy for breast cancer brain metastasis patients with activating mutations in the PI3K pathway. These data provide a rationale to further evaluate the efficacy of GDC-0068 in patients with brain metastases. (© The Author(s) 2019. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
Databáze:	MEDLINE
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