Antitumor activity of the novel multi-kinase inhibitor EC-70124 in triple negative breast cancer

Abstract

Disseminated triple negative breast cancer (TNBC) is an incurable disease with limited therapeutic options beyond chemotherapy. Therefore, identification of druggable vulnerabilities is an important aim. Protein kinases play a central role in cancer and particularly in TNBC. They are involved in many oncogenic functions including migration, proliferation, genetic stability or maintenance of stem-cell like properties. In this article we describe a novel multi-kinase inhibitor with antitumor activity in this cancer subtype. EC-70124 is a hybrid indolocarbazole analog obtained by combinatorial biosynthesis of Rebeccamycin and Staurosporine genes that showed antiproliferative effect and in vivo antitumoral activity. Biochemical experiments demonstrated the inhibition of the PI3K/mTOR and JAK/STAT pathways. EC-70124 mediated DNA damage leading to cell cycle arrest at the G2/M phase. Pathway analyses identified several deregulated functions including cell proliferation, migration, DNA damage, regulation of stem cell differentiation and reversion of the epithelial-mesenchymal transition (EMT) phenotype, among others. Combination studies showed a synergistic interaction of EC-70124 with docetaxel, and an enhanced activity in vivo. Furthermore, EC-70124 had a good pharmacokinetic profile. In conclusion these experiments demonstrate the antitumor activity of EC-70124 in TNBC paving the way for the future clinical development of this drug alone or in combination with chemotherapy.

EC-70124, a Novel Glycosylated Indolocarbazole Multikinase Inhibitor, Reverts Tumorigenic and Stem Cell Properties in Prostate Cancer by Inhibiting STAT3 and NF-κB

“…Assays interrogating in vitro a large spectrum of kinases in the human kinome revealed that EC-70124 was highly active against IKK and JAK kinases (37,38). EC-70124 was also reported to inhibit NF-kB and JAK/STAT signaling, respectively, in glioblastoma cells (43) and in triple-negative breast cancer cells (38).…”

“…EC-70124 was also reported to inhibit NF-kB and JAK/STAT signaling, respectively, in glioblastoma cells (43) and in triple-negative breast cancer cells (38). However, the effects of EC-70124 on STAT3 and NFkB signaling and the consequences of concomitantly targeting these key transcription factors in cancer cells with constitutive activation of both pathways have not been investigated.…”

“…Prior studies indicated that the drug could be given safely by intravenous injection (38). Toxicity studies indicated that EC-70124 was could also be well tolerated when given orally.…”

“…In this series of novel glycosylated indolocarbazole compounds, EC-70124 (Fig. 1A) was of particular interest because it exhibited high activity toward IKK and JAK kinases, such as IKKb and JAK2, with IC 50 in the low nanomolar range (37,38). IKKb phosphorylates IkB, the inhibitory subunit that maintains the NF-kB complex in the inactive state in the cytoplasm (20).…”

IMiDs mobilize acute myeloid leukemia blasts to peripheral blood through downregulation of CXCR4 but fail to potentiate AraC/Idarubicin activity in preclinical models of non del5q/5q- AML

“…The cytotoxic effect of IMiDs on BM-MSCs was assessed using MTT assays as previously described. 21,22 Briefly, 2 × 10 4 cells were cultured with increasing drug concentrations in 96-well plates for 48 h. To determine the chemoprotective effect of BM-MSCs a total of 2 × 10 4 BM-MSCs were plated in 96-well plates 18 h before addition of AML cells (2 × 10 4 for cell lines and 2 × 10 5 for primary cells). BM-MSC:AML co-cultures were treated with IC 25 concentrations of the AraC (77nM) and Idarubicin (7nM) and 10 µM of lenalidomide/pomalidomide for 48–72 h. Apoptosis of CD33 + AML cells was measured using the annexin-V/7-AAD apoptosis detection kit (BD Biosciences) on a FACSCanto-II cytometer using FACSDiva software (BD Biosciences) as previously described.…”