Fatty acid synthase (FASN) as a therapeutic target in breast cancer

ABSTRACT

Introduction: Ten years ago, we put forward the metabolo-oncogenic nature of fatty acid synthase (FASN) in breast cancer. Since the conception of this hypothesis, which provided a model to explain how FASN is intertwined with various signaling networks to cell-autonomously regulate breast cancer initiation and progression, FASN has received considerable attention as a therapeutic target. However, despite the ever-growing evidence demonstrating the involvement of FASN as part of the cancer-associated metabolic reprogramming, translation of the basic science-discovery aspects of FASN blockade to the clinical arena remains a challenge.

Areas covered: Ten years later, we herein review the preclinical lessons learned from the pharmaceutical liabilities of the first generation of FASN inhibitors. We provide an updated view of the current development and clinical testing of next generation FASN-targeted drugs. We also discuss new clinico-molecular approaches that should help us to convert roadblocks into roadways that will propel forward our therapeutic understanding of FASN.

Expert opinion: With the recent demonstration of target engagement and early signs of clinical activity with the first orally available, selective, potent and reversible FASN inhibitor, we can expect Big pharma to revitalize their interest in lipogenic enzymes as well-credentialed targets for oncology drug development in breast cancer.

KEYWORDS:

• Breast cancer
• fatty acid synthase
• lipogenesis
• therapeutics
• HER2
• obesity

Article highlights

• The lipogenic enzyme FASN is part of the metabolic reprogramming cancer hallmark.

• Most of the first generation FASN inhibitors described in the literature should be viewed as tool compounds rather than clinically valuable oncology drugs.

• The apparent discrepancy between bench findings and the awaited bedside effects has remained an elusive challenge until recently.

• We are celebrating the fact that next generation FASN-targeted drugs with optimized pharmacological properties and in vivo tolerability has just entered the clinic.

• We anticipate that additional FASN inhibitors will be integrated into an expanding pipeline of targeted drugs based on an ever-growing understanding of the FASN biology-breast cancer association.

• We can expect big pharma to revitalize their interest in lipogenic enzymes as well-credentialed targets for oncology drug development in breast cancer.

This box summarizes key points contained in the article.

Acknowledgments

The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Department of Defense, the United States government, or the National Institutes of Health.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This work was supported by grants from the National Institute of Health (NIH), National Cancer Institute (NCI) RO1CA116623-10, The Mayo Clinic Cancer Center Foundation, and the Department of Defense Breast Cancer Research Program award W81XWH-04-1-0759 to R. Lupu. This work was also supported by grants from the Ministerio de Ciencia e Innovación (Grant SAF2016-80639-P to J. A. Menendez), Plan Nacional de I+D+I, Spain and the Agència de Gestió d’Ajuts Universitaris i de Recerca (AGAUR) (Grant 2014 SGR229 to J. A. Menendez), Departament d’Economia i Coneixement, Catalonia, Spain. The Metabolism & Cancer laboratory is supported by an unrestricted grant from the Armangué family (Girona, Catalonia).