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Targeting Mcl-1 for the therapy of cancer

Bridget A Quinn Virginia Commonwealth University, School of Medicine, Department of Human and Molecular Genetics, Richmond, VA, [email protected]

Rupesh Dash Virginia Commonwealth University, School of Medicine, Department of Human and Molecular Genetics, Richmond, VA, [email protected]

Belal Azab Virginia Commonwealth University, School of Medicine, Department of Human and Molecular Genetics, Richmond, VA, [email protected]

Siddik Sarkar Virginia Commonwealth University, School of Medicine, Department of Human and Molecular Genetics, Richmond, VA, [email protected]

Swadesh K Das Virginia Commonwealth University, School of Medicine, Department of Human and Molecular Genetics, Richmond, VA, [email protected]

Sachin Kumar Virginia Commonwealth University, School of Medicine, Department of Human and Molecular Genetics, Richmond, VA, [email protected]

Regina A Oyesanya Virginia Commonwealth University, School of Medicine, Department of Human and Molecular Genetics, Richmond, VA, [email protected]

Santanu Dasgupta Virginia Commonwealth University, School of Medicine, Department of Human and Molecular Genetics, Richmond, VA, [email protected]; Virginia Commonwealth University, VCU Institute of Molecular Medicine, School of Medicine, Richmond, VA, USA; Virginia Commonwealth University, VCU Massey Cancer Center, School of Medicine, Richmond, VA, USA

Paul Dent Virginia Commonwealth University, School of Medicine, Department of Neurosurgery, Richmond, VA, USA; Virginia Commonwealth University, VCU Institute of Molecular Medicine, School of Medicine, Richmond, VA, USA; Virginia Commonwealth University, VCU Massey Cancer Center, School of Medicine, Richmond, VA, USA

Steven Grant Virginia Commonwealth University, School of Medicine, Department of Medicine, Richmond, VA, USA; Virginia Commonwealth University, VCU Institute of Molecular Medicine, School of Medicine, Richmond, VA, USA; Virginia Commonwealth University, VCU Massey Cancer Center, School of Medicine, Richmond, VA, USA

Mohamed Rahmani Virginia Commonwealth University, School of Medicine, Department of Medicine, Richmond, VA, USA

David T Curiel Washington University School of Medicine, Department of Radiation Oncology, St. Louis, MO, USA

Igor Dmitriev Washington University School of Medicine, Department of Radiation Oncology, St. Louis, MO, USA

Michael Hedvat Virginia Commonwealth University, School of Medicine, Department of Human and Molecular Genetics, Richmond, VA, [email protected];Sanford-Burnham Medical Research Institute, La Jolla, CA, USA

Jun WeiSanford-Burnham Medical Research Institute, La Jolla, CA, USA

Bainan WuSanford-Burnham Medical Research Institute, La Jolla, CA, USA

John L StebbinsSanford-Burnham Medical Research Institute, La Jolla, CA, USA

John C ReedSanford-Burnham Medical Research Institute, La Jolla, CA, USA

Maurizio PellecchiaSanford-Burnham Medical Research Institute, La Jolla, CA, USA

Devanand Sarkar Virginia Commonwealth University, School of Medicine, Department of Human and Molecular Genetics, Richmond, VA, [email protected]; Virginia Commonwealth University, VCU Institute of Molecular Medicine, School of Medicine, Richmond, VA, USA; Virginia Commonwealth University, VCU Massey Cancer Center, School of Medicine, Richmond, VA, USA

Paul B Fisher Virginia Commonwealth University, School of Medicine, Department of Human and Molecular Genetics, Richmond, VA, [email protected]; Virginia Commonwealth University, VCU Institute of Molecular Medicine, School of Medicine, Richmond, VA, USA; Virginia Commonwealth University, VCU Massey Cancer Center, School of Medicine, Richmond, VA, USA

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Abstract

Introduction: Human cancers are genetically and epigenetically heterogeneous and have the capacity to commandeer a variety of cellular processes to aid in their survival, growth and resistance to therapy. One strategy is to overexpress proteins that suppress apoptosis, such as the Bcl-2 family protein Mcl-1. The Mcl-1 protein plays a pivotal role in protecting cells from apoptosis and is overexpressed in a variety of human cancers.

Areas covered: Targeting Mcl-1 for extinction in these cancers, using genetic and pharmacological approaches, represents a potentially effectual means of developing new efficacious cancer therapeutics. Here we review the multiple strategies that have been employed in targeting this fundamental protein, as well as the significant potential these targeting agents provide in not only suppressing cancer growth, but also in reversing resistance to conventional cancer treatments.

Expert opinion: We discuss the potential issues that arise in targeting Mcl-1 and other Bcl-2 anti-apoptotic proteins, as well problems with acquired resistance. The application of combinatorial approaches that involve inhibiting Mcl-1 and manipulation of additional signaling pathways to enhance therapeutic outcomes is also highlighted. The ability to specifically inhibit key genetic/epigenetic elements and biochemical pathways that maintain the tumor state represent a viable approach for developing rationally based, effective cancer therapies.

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Targeting Mcl-1 for the therapy of cancer

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Targeting Mcl-1 for the therapy of cancer

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