Oncotarget

Research Papers:

TAK228 enhances antitumor activity of eribulin in triple negative breast cancer

Nicci Owusu-Brackett, Kurt W. Evans, Argun Akcakanat, Erkan Yuca, Coya Tapia, Yasmeen Qamar Rizvi, Ecaterina Ileana Dumbrava, Filip Janku and Funda Meric-Bernstam _

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Oncotarget. 2019; 10:5011-5019. https://doi.org/10.18632/oncotarget.27082

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Abstract

Nicci Owusu-Brackett1,2, Kurt W. Evans3, Argun Akcakanat3, Erkan Yuca3, Coya Tapia4, Yasmeen Qamar Rizvi3, Ecaterina Ileana Dumbrava3, Filip Janku3 and Funda Meric-Bernstam3,5,6

1 Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA

2 Current address: Department of General Surgery, The University of Texas Health San Antonio, San Antonio, TX 78229, USA

3 Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA

4 Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA

5 Department of Breast Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA

6 The Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA

Correspondence to:

Funda Meric-Bernstam,email: [email protected]

Keywords: breast cancer; TAK228; PI3K; PTEN; TNBC

Received: January 08, 2019     Accepted: June 29, 2019     Published: August 20, 2019

ABSTRACT

Background: Phosphatase and tensin homologue deleted from chromosome 10 (PTEN) negatively regulates the phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR pathway. Triple negative breast cancers (TNBC) are often PTEN-deficient, making mTOR a compelling target. We evaluated the efficacy of catalytic mTOR inhibitor TAK228 alone and in combination with eribulin in TNBC.

Results: Five of eight triple negative breast cell lines were sensitive to TAK228, independent of PIK3CA/PTEN status. Western blotting demonstrated inhibition of mTORC1/2 signaling as demonstrated by decreased phospho-AKT, phospho-S6 and phospho-4EBP1. In vitro, TAK228 was synergistic with eribulin in all eight TNBC cell lines. The combination of TAK228 and eribulin did not enhance apoptosis but increased G2/M growth arrest. In vivo, TAK228 led to modest growth inhibition in TNBC patient-derived xenografts (PDXs) with no tumor regression observed. In two TNBC PDXs with PTEN loss, one with intrinsic eribulin sensitivity, another eribulin resistance, TAK228 in combination with eribulin did not enhance in vivo efficacy. In a third PTEN-negative TNBC model, eribulin alone achieved disease stabilization, but the combination of TAK228 and eribulin led to significantly smaller tumor volumes compared to eribulin alone (p < 0.001).

Methods: We tested in vitro efficacy of TAK228 in a panel of TNBC cell lines with cell proliferation assays. In vivo antitumor efficacy of TAK228 was evaluated alone and in combination with eribulin.

Conclusion: TAK228 enhances the antitumor efficacy of eribulin in TNBC models in vitro, and enhanced in vivo activity in selected models. Further study is needed to determine the potential of this combination, and optimal patient selection strategies.


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