Abstract

BackgroundThe activation of the MAPK and PI3K/AKT/mTOR pathways is implicated in the majority of cancers. Activating mutations in both of these pathways has been described in colorectal cancer (CRC), thus indicating their potential as therapeutic targets. This study evaluated the combination of a PI3K/mTOR inhibitor (PF-04691502/PF-502) in combination with a MEK inhibitor (PD-0325901/PD-901) in CRC cell lines and patient-derived CRC tumor xenograft models (PDTX).Materials and MethodsThe anti-proliferative effects of PF-502 and PD-901 were assessed as single agents and in combination against a panel of CRC cell lines with various molecular backgrounds. Synergy was evaluated using the Bliss Additivity method. In selected cell lines, we investigated the combination effects on downstream effectors by immunoblotting. The combination was then evaluated in several fully genetically annotated CRC PDTX models.ResultsThe in vitro experiments demonstrated a wide range of IC50 values for both agents against a cell line panel. The combination of PF-502 and PD-901 demonstrated synergistic anti-proliferative activity with Bliss values in the additive range. As expected, p-AKT and p-ERK were downregulated by PF-502 and PD-901, respectively. In PDTX models, following a 30-day exposure to PF-502, PD-901 or the combination, the combination demonstrated enhanced reduction in tumor growth as compared to either single agent regardless of KRAS or PI3K mutational status.ConclusionsThe combination of a PI3K/mTOR and a MEK inhibitor demonstrated enhanced anti-proliferative effects against CRC cell lines and PDTX models.

Highlights

  • Two of the most implicated cellular pathways in cancers are the phosphatidylinositol-3 kinases (PI3K) and the mitogen activated protein kinase (MAPK) pathways

  • To explore the efficacy of simultaneous inhibition of both the PI3K-AKT-mammalian target of rapamycin (mTOR) and the RAS-RAF-MEK pathways, we examined the combination of PF-04691502 (PF-502) with PD0325901 (PD-901)

  • colorectal cancer (CRC) cell lines were exposed to increasing concentrations of PF502 and PD-901 for 72 hours, proliferation was assessed and IC50 values were calculated from average proliferation of triplicate experiments

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Summary

Introduction

Two of the most implicated cellular pathways in cancers are the phosphatidylinositol-3 kinases (PI3K) and the mitogen activated protein kinase (MAPK) pathways. In colorectal cancer (CRC), the PIK3CA gene, encoding the p110a catalytic subunit of class I PI3Ks, has been found to be mutated in 10–20% of CRC tumor specimens [5]. A downstream component of the PI3K signaling pathway is the mammalian target of rapamycin (mTOR). The activation of the MAPK and PI3K/AKT/mTOR pathways is implicated in the majority of cancers. Activating mutations in both of these pathways has been described in colorectal cancer (CRC), indicating their potential as therapeutic targets. This study evaluated the combination of a PI3K/mTOR inhibitor (PF-04691502/PF-502) in combination with a MEK inhibitor (PD-0325901/PD-901) in CRC cell lines and patient-derived CRC tumor xenograft models (PDTX)

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