Targeting AKT for cancer therapy

ABSTRACT

Introduction: Targeted therapies in cancer aim to inhibit specific molecular targets responsible for enhanced tumor growth. AKT/PKB (protein kinase B) is a serine threonine kinase involved in several critical cellular pathways, including survival, proliferation, invasion, apoptosis, and angiogenesis. Although phosphatidylinositol-3 kinase (PI3K) is the key regulator of AKT activation, numerous stimuli and kinases initiate pro-proliferative AKT signaling which results in the activation of AKT pathway to drive cellular growth and survival. Activating mutations and amplification of components of the AKT pathway are implicated in the pathogenesis of many cancers including breast and ovarian. Given its importance, AKT, it has been validated as a promising therapeutic target.

Areas covered: This article summarizes AKT’s biological function and different classes of AKT inhibitors as anticancer agents. We also explore the efficacy of AKT inhibitors as monotherapies and in combination with cytotoxic and other targeted therapies.

Expert opinion: The complex mechanism following AKT inhibition requires the addition of other therapies to prevent resistance and improve clinical response. Further studies are necessary to determine additional rational combinations that can enhance efficacy of AKT inhibitors, potentially by targeting compensatory mechanisms, and/or enhancing apoptosis. The identification of biomarkers of response is essential for the development of successful therapeutics.

KEYWORDS:

• AKT activation
• tumorigenicity
• breast and ovarian cancer
• AKT inhibitors
• targeted therapy
• combinational therapy

Article highlights

• Aberrant activation of AKT plays an important role in the pathogenesis of many human tumors, including breast and ovarian cancers.

• Many compounds have been developed to inhibit AKT as a validated therapeutic target.

• Tumors with PI3K/AKT pathway genomic alterations demonstrated more sensitivity to AKT inhibitions.

• Combining AKT inhibitors with other therapeutic agents can greatly enhance the efficacy of these inhibitors.

• the identification of targeted agents and their predictive biomarkers is necessary for the development of successful therapeutic strategies.

This box summarizes key points contained in the article.

Acknowledgments

We thank Visual Art at the University of Texas, MD Anderson Cancer Center for generating the illustration in Figure 1.

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.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose

Additional information

Funding

The work of the authors was supported in part by the Nellie B. Connally Breast Cancer Research Endowment, The Cancer Prevention and Research Institute of Texas RP150535, Sheikh Khalifa Al Nahyan Ben Zayed Institute for Personalized Cancer Therapy, MD Anderson Cancer Center Support grant (P30 CA016672).