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The Enhanced In Vivo Activity of the Combination of a MEK and a PI3K Inhibitor Correlates with [¹⁸F]-FLT PET in Human Colorectal Cancer Xenograft Tumour-Bearing Mice

Lookup NU author(s): Dr Emma Haagensen, Huw ThomasORCiD, Ian Wilson, Dr Suzannah HarnorORCiD, Sara Payne, Dr Tommy Rennison, Dr Kate Smith, Dr Ross Maxwell, Professor Herbie Newell

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).

Abstract

Combined targeting of the MAPK and PI3K signalling pathways in cancer may be necessary for optimal therapeutic activity. To support clinical studies of combination therapy, 39-deoxy-39-[F-18]-fluorothymidine ([F-18]-FLT) uptake measured by Positron Emission Tomography (PET) was evaluated as a non-invasive surrogate response biomarker in pre-clinical models. The in vivo anti-tumour efficacy and PK-PD properties of the MEK inhibitor PD 0325901 and the PI3K inhibitor GDC-0941, alone and in combination, were evaluated in HCT116 and HT29 human colorectal cancer xenograft tumour-bearing mice, and [F-18]-FLT PET investigated in mice bearing HCT116 xenografts. Dual targeting of PI3K and MEK induced marked tumour growth inhibition in vivo, and enhanced anti-tumour activity was predicted by [18 F]-FLT PET scanning after 2 days of treatment. Pharmacodynamic analyses using the combination of the PI3K inhibitor GDC-0941 and the MEK inhibitor PD 0325901 revealed that increased efficacy is associated with an enhanced inhibition of the phosphorylation of ERK1/2, S6 and 4EBP1, compared to that observed with either single agent, and maintained inhibition of AKT phosphorylation. Pharmacokinetic studies indicated that there was no marked PK interaction between the two drugs. Together these results indicate that the combination of PI3K and MEK inhibitors can result in significant efficacy, and demonstrate for the first time that [F-18]-FLT PET can be correlated to the improved efficacy of combined PI3K and MEK inhibitor treatment.

Publication metadata

Author(s): Haagensen EJ, Thomas HD, Wilson I, Harnor SJ, Payne SL, Rennison T, Smith KM, Maxwell RJ, Newell DR

Publication type: Article

Publication status: Published

Journal: PLoS ONE

Year: 2013

Volume: 8

Issue: 12

Print publication date: 10/12/2013

Acceptance date: 16/10/2013

Date deposited: 24/03/2014

ISSN (electronic): 1932-6203

Publisher: Public Library of Science

URL: http://dx.doi.org/10.1371/journal.pone.0081763

DOI: 10.1371/journal.pone.0081763

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