PI3K inhibition enhances the anti-tumor effect of eribulin in triple negative breast cancer
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Sandeep Rajput1, Zhanfang Guo1, Shunqiang Li1,2 and Cynthia X. Ma1,2
1 Section of Medical Oncology, Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
2 Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO 63110, USA
|Cynthia X. Ma,||email:||firstname.lastname@example.org|
Keywords: PI3K inhibitor; BKM120; eribulin; triple-negative breast cancer; patient-derived xenograft
Received: March 18, 2019 Accepted: April 29, 2019 Published: June 04, 2019
Loss of the tumor suppressor phosphatase and tensin homolog (PTEN) is commonly observed in triple negative breast cancer (TNBC), leading to activation of the phosphoinositide 3-kinase (PI3K) signaling to promote tumor cell growth and chemotherapy resistance. In this study, we investigated whether adding a pan-PI3K inhibitor could improve the cytotoxic effect of eribulin, a non-taxane microtubule inhibitor, in TNBC patient-derived xenograft models (PDX) with loss of PTEN, and the underlying molecular mechanisms. Three TNBC-PDX models (WHIM6, WHIM12 and WHIM21), all with loss of PTEN expression, were tested for their response to BKM120 and eribulin, alone or in combination in vivo. In addition, the effect of drug treatment on cell proliferation and cell cycle progression were also performed in vitro using a panel of TNBC cell lines, including 2 derived from PDX models. The combination of eribulin and BKM120 led to additive or synergistic anti-tumor effect in 2 of the 3 PDX models, accompanied by an enhanced mitotic arrest and apoptosis in sensitive PDX models. In addition, the combination was synergistic in reducing mammosphere formation, and markers for epithelial-mesenchymal transition (EMT). In conclusion, PI3K inhibition induces synergistic anti-tumor effect when combined with eribulin, by enhancing mitotic arrest and apoptosis, as well as, reducing the cancer stem cell population. This study provides a preclinical rationale to investigate the therapeutic potential for the combination of PI3K inhibition and eribulin in the difficult to treat TNBC. Further studies are needed to identify the biomarkers of response for target patient selection.
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