Enhanced anti-tumour activity of the combination of the novel MEK inhibitor WX-554 and the novel PI3K inhibitor WX-037

Abstract

PurposeTumours frequently have defects in multiple oncogenic pathways, e.g. MAPK and PI3K signalling pathways, and combinations of targeted therapies may be required for optimal activity. This study evaluated the novel MEK inhibitor WX-554 and the novel PI3K inhibitor WX-037, as single agents and in combination, in colorectal carcinoma cell lines and tumour xenograft-bearing mice.MethodsIn vitro growth inhibition, survival and signal transduction were measured using the Sulforhodamine B, clonogenic and Western blotting assays, respectively, in HCT116 and HT29 cell lines. In vivo anti-tumour efficacy and pharmacokinetic properties were assessed in HCT116 and HT29 human colorectal cancer xenograft tumour-bearing mice.ResultsThe combination of WX-554 and WX-037 exhibited marked synergistic growth inhibition in vitro, which was associated with increased cytotoxicity and enhanced inhibition of ERK and S6 phosphorylation, compared to either agent alone. Pharmacokinetic analyses indicated that there was no PK interaction between the two drugs at low doses, but that at higher doses, WX-037 may delay the tumour uptake of WX-554. In vivo efficacy studies revealed that the combination of WX-037 and WX-554 was non-toxic and exhibited marked tumour growth inhibition greater than observed with either agent alone.ConclusionThese studies show for the first time that combination treatment with the novel MEK inhibitor WX-554 and the novel PI3K inhibitor WX-037 can induce synergistic growth inhibition in vitro, which translates into enhanced anti-tumour efficacy in vivo.Electronic supplementary materialThe online version of this article (doi:10.1007/s00280-016-3186-4) contains supplementary material, which is available to authorized users.

High-throughput screening reveals higher synergistic effect of MEK inhibitor combinations in colon cancer spheroids

“…3a). www.nature.com/scientificreports/ The combinations found to be synergistic included the well-documented combination effect of co-targeting PI3K and MEK [25][26][27] as well as combined application of the PI3K inhibitor with the TAK1 inhibitor, previously reported by us 28 and later also by others 29 . The clinically approved combination of oxaliplatin (OXA) with 5-fluorouracil (5-FU) 30 was found to be synergistic at low doses of oxaliplatin across all cell lines, albeit with low efficacy of only reducing viability to < 0.5 in 2D-cultured HCT-116 cells.…”

MEK inhibitors in cancer treatment: structural insights, regulation, recent advances and future perspectives

“…103 Unfortunately, for commercial reasons, two dose-escalation phase I/II studies in patients with advanced solid tumours were stopped. 104 KZ-02 was developed for MEK inhibition, and causes the upregulation of Pim-1. Although KZ-02 increases the mRNA expression of Pim-1, it also promotes the proteasomal degradation of Pim-1.…”

Targeting Signaling Pathway Networks in Several Malignant Tumors: Progresses and Challenges

“…Consequently, four major kinds of drugs that target the PI3K/AKT/mTOR pathway have been identified (Table 3): PI3K, AKT, PI3K/mTOR, and mTOR inhibitors. The PI3K inhibitors BKM120 (Yang et al, 2018a), PX-886 (Yang et al, 2018b), XL147 (Gravina et al, 2016), WX-037 (Haagensen et al, 2016), BYL719 (Juric et al, 2018), and GDC0032 (Juric et al, 2018) were designed treat gastric cancer. PI3K/mTOR inhibitors include P7170 (Jalota-Badhwar et al, 2015), BEZ235 (Kim et al, 2019), XL765 (Gravina et al, 2016), GDC-0980 (Kim et al, 2019), SF1126 (Kim et al, 2019), PF-05212384 (Kim et al, 2019), PF-4691502 (Kim et al, 2019), and VS-558 (Kim et al, 2019).…”