Dual PI3K and Wnt pathway inhibition is a synergistic combination against triple negative breast cancer

Jeffrey P. Solzak, Rutuja V. Atale, Bradley A. Hancock, Anthony L. Sinn, Karen E. Pollok, David R. Jones, Milan Radovich

Research output: Contribution to journalArticle

14 Scopus citations

Abstract

Triple negative breast cancer accounts for 15-20% of all breast cancer cases, but despite its lower incidence, contributes to a disproportionately higher rate of mortality. As there are currently no Food and Drug Administration-approved targeted agents for triple negative breast cancer, we embarked on a genomic-guided effort to identify novel targeted modalities. Analyses by our group and The Cancer Genome Atlas have identified activation of the PI3K-pathway in the majority of triple negative breast cancers. As single agent therapy is commonly subject to resistance, we investigated the use of combination therapy against compensatory pathways. Herein, we demonstrate that pan-PI3K inhibition in triple negative breast cancers results in marked activation of the Wnt-pathway. Using the combination of two inhibitors currently in clinical trial as single agents, buparlisib(panPI3K) and WNT974(WNT-pathway), we demonstrate significant in vitro and in vivo synergy against triple negative breast cancer cell lines and xenografts. Taken together, these observations provide a strong rationale for testing dual targeting of the PI3K and WNTpathways in clinical trials.

Original languageEnglish (US)
Article number0016
Journalnpj Breast Cancer
Volume3
Issue number1
DOIs
StatePublished - Dec 1 2017

ASJC Scopus subject areas

  • Oncology
  • Radiology Nuclear Medicine and imaging
  • Pharmacology (medical)

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