TY - JOUR
T1 - TAK228 enhances antitumor activity of eribulin in triple negative breast cancer
AU - Owusu-Brackett, Nicci
AU - Evans, Kurt W.
AU - Akcakanat, Argun
AU - Yuca, Erkan
AU - Tapia, Coya
AU - Rizvi, Yasmeen Qamar
AU - Dumbrava, Ecaterina Ileana
AU - Janku, Filip
AU - Meric-Bernstam, Funda
N1 - Funding Information:
This work was supported by National Institutes of Health (NIH) T32 CA009599 (NOB, FMB), NIH University of Texas PDX Development and Trial Center U54CA224065 (FMB, KE), NIH Southwest Early Clinical Trials Consortium UM1CA186688 (FMB, KE), MD Anderson Women’s Cancers Moonshot Program (KE, FMB), the Nellie B. Connally Breast Cancer Research Endowment (KE, EY, SS, FMB), the Barr funds, and the MD Anderson Cancer Center Support Grant (P30 CA016672).
Publisher Copyright:
© 2019 Owusu-Brackett et al.
PY - 2019
Y1 - 2019
N2 - 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.
AB - 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.
KW - Breast cancer
KW - PI3K
KW - PTEN
KW - TAK228
KW - TNBC
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U2 - 10.18632/oncotarget.27082
DO - 10.18632/oncotarget.27082
M3 - Article
C2 - 31489111
AN - SCOPUS:85071634997
SN - 1949-2553
VL - 10
SP - 5011
EP - 5019
JO - Oncotarget
JF - Oncotarget
IS - 49
ER -