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

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.

SUBMITTER: Rajput S

PROVIDER: S-EPMC6557212 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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

Rajput Sandeep S Guo Zhanfang Z Li Shunqiang S Ma Cynthia X CX

Oncotarget 20190604 38

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 molec ...[more]

PMID: 31217901

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Project description:Triple-negative breast cancer (TNBC) is an aggressive subtype defined by lack of hormone receptor expression and non-amplified HER2. Adavosertib (AZD1775) is a potent, small-molecule, ATP-competitive inhibitor of the Wee1 kinase that potentiates the activity of many DNA-damaging chemotherapeutics and is currently in clinical development for multiple indications. The purpose of this study was to investigate the combination of AZD1775 and capecitabine/5FU in preclinical TNBC models. TNBC cell lines were treated with AZD1775 and 5FU and cellular proliferation was assessed in real-time using IncuCyte® Live Cell Analysis. Apoptosis was assessed via the Caspase-Glo 3/7 assay system. Western blotting was used to assess changes in expression of downstream effectors. TNBC patient-derived xenograft (PDX) models were treated with AZD1775, capecitabine, or the combination and assessed for tumor growth inhibition. From the initial PDX screen, two of the four TNBC PDX models demonstrated a better response in the combination treatment than either of the single agents. As confirmation, two PDX models were expanded for statistical comparison. Both PDX models demonstrated a significant growth inhibition in the combination versus either of the single agents. (TNBC012, p < 0.05 combo vs. adavosertib or capecitabine, TNBC013, p < 0.01 combo vs. adavosertib or capecitabine.) An enhanced anti-proliferative effect was observed in the adavosertib/5FU combination treatment as measured by live cell analysis. An increase in apoptosis was observed in two of the four cell lines in the combination when compared to single-agent treatment. Treatment with adavosertib as a single agent resulted in a decrease in p-CDC2 in a dose-dependent manner that was also observed in the combination treatment. An increase in γH2AX in two of the four cell lines tested was also observed. No significant changes were observed in Bcl-xL following treatment in any of the cell lines. The combination of adavosertib and capecitabine/5FU demonstrated enhanced combination effects both in vitro and in vivo in preclinical models of TNBC. These results support the clinical investigation of this combination in patients with TNBC, including those with brain metastasis given the CNS penetration of both agents.

Project description:BACKGROUND:Protein kinase C theta, (PRKCQ/PKC?) is a serine/threonine kinase that is highly expressed in a subset of triple-negative breast cancers (TNBC) and promotes their growth, anoikis resistance, epithelial-mesenchymal transition (EMT), and invasion. Here, we show that PRKCQ regulates the sensitivity of TNBC cells to apoptosis triggered by standard-of-care chemotherapy by regulating levels of pro-apoptotic Bim. METHODS:To determine the effects of PRKCQ expression on chemotherapy-induced apoptosis, shRNA and cDNA vectors were used to modulate the PRKCQ expression in MCF-10A breast epithelial cells or triple-negative breast cancer cells (MDA-MB231Luc, HCC1806). A novel PRKCQ small-molecule inhibitor, 17k, was used to inhibit kinase activity. Viability and apoptosis of cells treated with PRKCQ cDNA/shRNA/inhibitor +/-chemotherapy were measured. Expression levels of Bcl2 family members were assessed. RESULTS:Enhanced expression of PRKCQ is sufficient to suppress apoptosis triggered by paclitaxel or doxorubicin treatment. Downregulation of PRKCQ also enhanced the apoptosis of chemotherapy-treated TNBC cells. Regulation of chemotherapy sensitivity by PRKCQ mechanistically occurs via regulation of levels of Bim, a pro-apoptotic Bcl2 family member; suppression of Bim prevents the enhanced apoptosis observed with combined PRKCQ downregulation and chemotherapy treatment. Regulation of Bim and chemotherapy sensitivity is significantly dependent on PRKCQ kinase activity; overexpression of a catalytically inactive PRKCQ does not suppress Bim or chemotherapy-associated apoptosis. Furthermore, PRKCQ kinase inhibitor treatment suppressed growth, increased anoikis and Bim expression, and enhanced apoptosis of chemotherapy-treated TNBC cells, phenocopying the effects of PRKCQ downregulation. CONCLUSIONS:These studies support PRKCQ inhibition as an attractive therapeutic strategy and complement to chemotherapy to inhibit the growth and survival of TNBC cells.

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

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

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