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PI3K and MEK inhibitor combinations: examining the evidence in selected tumor types

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Abstract

The PI3K/AKT/mTOR and RAS/RAF/MEK/ERK pathways are two of the most frequently dysregulated kinase cascades in human cancer. Molecular alterations in these pathways are implicated in tumorigenesis and resistance to anticancer therapies. The PI3K/AKT/mTOR and RAS/RAF/MEK/ERK pathways are known to interact with each other at several nodes, and mounting evidence suggests that dual blockade of both pathways may be required to achieve anticancer effects in certain contexts. This may include tumor types with a high frequency of RAS/RAF/MEK/ERK pathway activation, or situations in which dual pathway strategies may be required to overcome resistance to current targeted therapies. Several clinical studies are currently evaluating the combination of PI3K and MEK inhibitors in a variety of different cancers with certain types of molecular alterations. This review will summarize existing knowledge of the PI3K/AKT/mTOR and RAS/RAF/MEK/ERK pathways, the cross-talk between them, and the current generation of PI3K and MEK inhibitors that target them. The preclinical rationale for dual pathway inhibition will be discussed within the context of the major tumor types currently being explored in ongoing clinical trials, namely malignant melanoma with BRAF or NRAS mutations, and colorectal, ovarian, pancreatic, and basal-like breast cancers. The emerging clinical profile of PI3K and MEK inhibitor combinations, as reported in Phase I trials, will also be discussed.

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Acknowledgments

Financial support for medical editorial assistance was provided by Novartis Pharmaceuticals. Ben Holtom DPhil provided medical editorial assistance with this manuscript. The author retained full editorial control over the content of the manuscript and received no compensation from any party for this work. Carolyn Britten is appointed as the SmartState Endowed Chair in GI Malignancy Diagnostic & Therapeutic Trials in the South Carolina SmartState® Center for Gastrointestinal Cancer Diagnostics. Carolyn Britten has received research funding from Bayer HealthCare Pharmaceuticals, Genentech, Novartis Pharmaceuticals, and Pfizer. She has received honoraria from Bayer HealthCare Pharmaceuticals.

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  1. Division of Hematology/Oncology, Department of Medicine, Hollings Cancer Center, Medical University of South Carolina, 96 Jonathan Lucas Street, Clinical Science Building, Suite 903, Charleston, SC, 29425, USA

    Carolyn D. Britten

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Britten, C.D. PI3K and MEK inhibitor combinations: examining the evidence in selected tumor types. Cancer Chemother Pharmacol 71, 1395–1409 (2013). https://doi.org/10.1007/s00280-013-2121-1

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