The dual PI3K/mTOR pathway inhibitor GDC-0084 achieves antitumor activity in PIK3CA-mutant breast cancer brain metastases

Franziska M. Ippen, Christopher A. Alvarez-Breckenridge, Benjamin M. Kuter, Alexandria L. Fink, Ivanna V. Bihun, Matthew Lastrapes, Tristan Penson, Stephen P. Schmidt, Gregory R. Wojtkiewicz, Jianfang Ning, Megha Subramanian, Anita Giobbie-Hurder, Maria Martinez-Lage, Scott L. Carter, Daniel P. Cahill, Hiroaki Wakimoto, Priscilla K. Brastianos

Research output: Contribution to journalArticle

10 Scopus citations

Abstract

Purpose: Previous studies have shown that the PI3K/Akt/ mTOR pathway is activated in up to 70% of breast cancer brain metastases, but there are no approved agents for affected patients. GDC-0084 is a brain penetrant, dual PI3K/mTOR inhibitor that has shown promising activity in a preclinical model of glioblastoma. The aim of this study was to analyze the efficacy of PI3K/mTOR blockade in breast cancer brain metastases models. Experimental Design: The efficacy of GDC-0084 was evaluated in PIK3CA-mutant and PIK3CA wild-type breast cancer cell lines and the isogenic pairs of PIK3CA wild-type and mutant (H1047R/þ) MCF10A cells in vitro. In vitro studies included cell viability and apoptosis assays, cell-cycle analysis, and Western blots. In vivo, the effect of GDC-0084 was investigated in breast cancer brain metastasis xenograft mouse models and assessed by bioluminescent imaging and IHC. Results: In vitro, GDC-0084 considerably decreased cell viability, induced apoptosis, and inhibited phosphorylation of Akt and p70 S6 kinase in a dose-dependent manner in PIK3CA-mutant breast cancer brain metastatic cell lines. In contrast, GDC-0084 led only to growth inhibition in PIK3CA wild-type cell lines in vitro. In vivo, treatment with GDC-0084 markedly inhibited the growth of PIK3CA-mutant, with accompanying signaling changes, and not PIK3CA wild-type brain tumors. Conclusions: The results of this study suggest that the brain-penetrant PI3K/mTOR targeting GDC-0084 is a promising treatment option for breast cancer brain metastases with dysregulated PI3K/mTOR signaling pathway conferred by activating PIK3CA mutations. A national clinical trial is planned to further investigate the role of this compound in patients with brain metastases.

Original languageEnglish (US)
Pages (from-to)3374-3383
Number of pages10
JournalClinical Cancer Research
Volume25
Issue number11
DOIs
StatePublished - Jun 1 2019
Externally publishedYes

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

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    Ippen, F. M., Alvarez-Breckenridge, C. A., Kuter, B. M., Fink, A. L., Bihun, I. V., Lastrapes, M., Penson, T., Schmidt, S. P., Wojtkiewicz, G. R., Ning, J., Subramanian, M., Giobbie-Hurder, A., Martinez-Lage, M., Carter, S. L., Cahill, D. P., Wakimoto, H., & Brastianos, P. K. (2019). The dual PI3K/mTOR pathway inhibitor GDC-0084 achieves antitumor activity in PIK3CA-mutant breast cancer brain metastases. Clinical Cancer Research, 25(11), 3374-3383. https://doi.org/10.1158/1078-0432.CCR-18-3049