PI3K inhibition enhances the anti-tumor effect of eribulin in triple negative breast cancer

Sandeep Rajput,Shunqiang Li,Cynthia X Ma,Zhanfang Guo

doi:10.18632/oncotarget.26960

Sandeep Rajput, Shunqiang Li + Show 2 more

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https://doi.org/10.18632/oncotarget.26960

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Abstract

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.

Highlights

Triple negative breast cancer (TNBC), defined by the lack of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) gene amplification, represents approximately 15 to 20% of all breast cancer cases and is associated with the worst prognosis compared to other breast cancer subtypes [1,2,3,4,5,6]
To assess the anti-tumor effect of BKM120 and eribulin, we tested a panel of triple negative breast cancer (TNBC) cell lines (BT549, HCC1806, and MDA-MB-231) as well as two patient-derived xenograft models (PDX) derived cell lines (WHIM3 and WHIM12), for their response to eribulin (0.1, 0.5 and 1nM) alone or in combination with BKM120 (500nM) in vitro
The combination reduced the level of the Epithelial to Mesenchymal Transition (EMT) marker N-Cadherin more effectively than eribulin alone, reduced the levels of the anti-apoptotic protein Survivin, and enhanced apoptosis as assessed by cleaved PARP (Figure 1F)

Summary

Introduction

Triple negative breast cancer (TNBC), defined by the lack of estrogen receptor (ER), progesterone receptor (PR) and HER2 gene amplification, represents approximately 15 to 20% of all breast cancer cases and is associated with the worst prognosis compared to other breast cancer subtypes [1,2,3,4,5,6]. Eribulin mesylate (Halaven®, Eisai Inc) is a nontaxane microtubule dynamic inhibitor [7] that is Food and Drug Administration (FDA) approved for patients with metastatic breast cancer who have received at least two prior chemotherapeutic regimens in the metastatic setting and an anthracycline as well as a taxane in either adjuvant or metastatic setting. In the phase III EMBRACE study, eribulin was associated with superior overall survival (OS) compared with physician's choice chemotherapy in this patient population [8]. In addition to the induction of an www.oncotarget.com irreversible mitotic block, eribulin has been shown to impact tumor vascular remodeling [10] and inhibition of epithelial-to-mesenchymal transition and metastasis in experimental models [11] which has been implicated in www.oncotarget.com therapeutic resistance to cancer drugs including growth factor receptor and PI3K inhibitors [12]

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