Identification of Combinatorial Drugs that Synergistically Kill both Eribulin-Sensitive and Eribulin-Insensitive Tumor Cells

Abstract

Eribulin sensitivity was examined in a panel of twenty-five human cancer cell lines representing a variety of tumor types, with a preponderance of breast and lung cancer cell lines. As expected, the cell lines vary in sensitivity to eribulin at clinically relevant concentrations. To identify combination drugs capable of increasing anticancer effects in patients already responsive to eribulin, as well as inducing de novo anticancer effects in non-responders, we performed a combinatorial high throughput screen to identify drugs that combine with eribulin to selectively kill tumor cells. Among other observations, we found that inhibitors of ErbB1/ErbB2 (lapatinib, BIBW-2992, erlotinib), MEK (E6201, trametinib), PI3K (BKM-120), mTOR (AZD 8055, everolimus), PI3K/mTOR (BEZ 235), and a BCL2 family antagonist (ABT-263) show combinatorial activity with eribulin. In addition, antagonistic pairings with other agents, such as a topoisomerase I inhibitor (topotecan hydrochloride), an HSP-90 inhibitor (17-DMAG), and gemcitabine and cytarabine, were identified. In summary, the preclinical studies described here have identified several combination drugs that have the potential to either augment or antagonize eribulin's anticancer activity. Further elucidation of the mechanisms responsible for such interactions may be important for identifying valuable therapeutic partners for eribulin.of care. Chemotherapeutic drugs are often most effective when given in combination, in particular when synergistic killing is achieved without additive toxicity. To date, potential combination therapies for eribulin have been explored with only a limited number of anticancer agents. We therefore have performed an in vitro study of eribulin combined with 34 anticancer agents in 25 different tumor cell lines of various types, through use of a combination high throughput screening (cHTS) platform. Our goals were to identify drugs that might be paired with eribulin to increase clinical efficacy in metastatic breast cancer, to identify drugs that convert eribulin non-responders to responders, and to identify new therapeutic indications for eribulin utilization. Several compelling synergy effects with approved and emerging drugs were observed. The preclinical data provides insights about future clinical development strategies.

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

“…In this paper, we show that BKM120 enhances the cytotoxic effect of the non-taxane microtubule inhibitor eribulin in TNBC PDX models with loss of PTEN, accompanied by enhanced mitotic arrest and apoptosis induction. Our data provides in vivo validation for the synergistic effect of this combination observed in a cell-based assay [26] and is in line with a prior study presented in an abstract form in PIK3CA mutant breast cancer xenograft models [42]. These results are in support of ongoing and future clinical trial investigations of eribulin with PI3K pathway inhibitors such as NCT02723877 and NCT02616848 in this difficult to treat patient population.…”

“…PI3K pathway signaling activation has been identified to be a key resistance mechanism to chemotherapy as demonstrated in a recent study which investigated genomic alterations and gene expression profiles associated with chemotherapy resistance in patients with TNBC [36]. In addition, inhibition of PI3K pathway components has been shown to enhance the sensitivity to various chemotherapy agents in preclinical models [26,[37][38][39][40][41][42]. For example, significant synergisms in terms of reducing cell proliferation and induction of apoptosis were observed with the combination of ipatasertib, an AKT inhibitor, or taselisib, a PI3K inhibitor, and anti-microtubule agents including paclitaxel, vinorelbine, and eribulin in PIK3CA mutant breast cancer cell lines in vitro [40].…”

“…In addition, PI3K pathway activation has also been associated with chemotherapy resistance [22] and inhibition of PI3K pathway activity could synergize the cytotoxicity of a variety of chemotherapy agents [23][24][25]. In a cell-based, high-throughput screening in a panel of twenty-five human cancer cell lines representing a variety of tumor types, the PI3K inhibitor BKM120 was identified to exert synergistic killing with eribulin in both eribulin sensitive and resistant cancer cell lines, 3 of which being TNBC [26]. The objectives of this study is to assess the combinatory effect of eribulin and BKM120 in TNBC cell lines and patient-derived xenograft (PDX) models and to further elucidate the underlying molecular mechanisms.…”

A Flexible, Pooled CRISPR Library for Drug Development Screens

“…(For detailed methods see Kondo et al 2002. 28 ) Pharmacogenomic analysis of response was performed using the mRNA expression and CRISPRko gene dependency data obtained from the Cancer Dependency Map (Depmap) portal release 2019q3. Correlation between drug response and PARP1 expression was analyzed by Pearson correlation.…”