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.

Investigating the Role of CTCs with Stem/EMT-like Features in Metastatic Breast Cancer Patients Treated with Eribulin Mesylate

“…The discrepancy between our results and the in vitro evidence in Kurebayashi et al [ 16 ] could be attributed to the relatively small number of CTCs analyzed, the significant heterogeneity of CTCs as compared to cell lines, and the different methodologies employed that could possibly identify different CSC-like populations displaying distinct properties. On the other hand, our findings corroborate preclinical findings in BC, showing that eribulin resistance is promoted by the activation of the PI3K/AKT pathway [ 21 ], which holds a key role in maintaining the stemness of BC cells [ 22 ], and that the combination of eribulin with PI3K inhibition has synergistic antitumor effects by reducing the breast CSC population [ 30 ]. The role of CSCs in primary and acquired resistance to eribulin needs further investigation in BC patients, and analyses at the CTC level could be very informative in this regard.…”

Proteomic Resistance Biomarkers for PI3K Inhibitor in Triple Negative Breast Cancer Patient-Derived Xenograft Models

“…PDX models offer a unique resource for biomarker discovery. Several baseline biomarkers that were found to correlate with less responsiveness to BKM120 were reported previously in association with PI3K inhibitor resistance, for example upregulated RTK [ 26 , 27 ], EMT [ 28 , 29 ], and anti-apoptotic signaling [ 30 ]. However, other markers including PI3Kp85 regulatory subunit, NFKB pathway (IkappaB, RANKL), and intracellular signaling molecules including Caveolin, CBP, and KLF4 are also identified, which could represent potential novel resistance mechanisms.…”

RNA-sequencing and microarray data mining revealing: the aberrantly expressed mRNAs were related with a poor outcome in the triple negative breast cancer patients

“…Furthermore, the enriched biological pathways of the DEGs we selected included MET, mTOR signaling pathway and IL-3 mediated signaling pathway. Numerous studies had reported epithelial-to-mesenchymal transition (EMT) can be induced by receptor tyrosine kinases (RTKs) including c-Met, epithelial growth factorreceptors and IGF-1R, and EMT always promoted tumor progression, in development of carcinoma, RAF/ MEK/ERK1/2 axis, PI3k/Akt/mTOR pathways, and phosphorylation of β-catenin were play a critical role (39)(40)(41). Function analysis helps us better to understand the mechanism of TNBC and provides a guide for TNBC prevention and treatment; however, further laboratory and clinical researchers are required to verify this.…”