The PI 3-Kinase and AKT Signaling Pathway in Biology and Disease: From Discovery to Therapeutics

Hosts: Ralitsa Madsen and Dario Alessi

Venue: MSI Small Lecture Theatre, SLS

Abstract:

The PI 3-kinase (PI3K) and AKT signaling pathway plays a critical role in regulating all aspects of normal cellular physiology, and is also frequently deregulated in human pathophysiologies, most evidently in cancer and diabetes. Growth factors and hormones stimulate PI3K leading to the biosynthesis of the lipid-derived second messenger PIP3. In turn, PIP3 elicits the membrane recruitment of the protein kinase AKT, originally discovered in 1987 by Staal and colleagues as v-Akt, a transforming oncogene. In the early 1990s, three independent groups cloned and described the cellular homolog c-AKT, a serine/threonine protein kinase with a high degree of homology to other AGC family protein kinases. In the ensuing three decades, the mechanisms by which AKT transduces signals to cell growth, proliferation, motility and metabolism were uncovered. Three AKT isoforms exist in humans encoded by distinct genes (AKT1, AKT2, AKT3), and although originally thought to function redundantly, many studies have shown that AKT isoforms have non-overlapping and unique roles in both normal physiology and disease. Similarly, genetic lesions in the PI3K and AKT oncogenes have been described, and many of the genes that contribute to PI3K/AKT pathway activation and also signal termination have been found to be altered in human cancers. Numerous drugs that inhibit PI3K as well AKT have been developed for therapeutic use in patients, and many of these are being evaluated in late-stage clinical trials. During the lecture, I will highlight the major advances in PI3K and AKT field over the past 30 years, with a focus on mechanistic insight into this ubiquitous lipid signaling pathway. Genetic lesions in the PI3K/AKT pathway in human cancers will also be discussed, as well as efforts to target this pathway therapeutically. The second part of the lecture will focus on recent efforts in our laboratory to uncover novel mechanisms of AKT signaling and biology, with an emphasis on breast cancer and with a focus on metabolic reprogramming mediated by AKT. I will also present recent efforts aimed at targeting AKT with novel therapies, including degrader technologies and how these have illuminated novel aspects of AKT biology. I will conclude with some personal thoughts and future perspectives as to where the field is going, gaps in knowledge and what studying AKT for 30 years has taught me.

Bio:

Alex Toker received a B.S. from King's College, University of London, and a PhD from the National Institute for Medical Research. He conducted post-doctoral research in the laboratory of Lewis Cantley in the Department of Medicine at BIDMC. He joined the faculty at the Boston Biomedical Research Institute in 1997 and in 2000 moved to Beth Israel Deaconess Medical Center and Harvard Medical School as an Assistant Professor in the Department of Pathology. In 2003, he was promoted to Associate Professor and joined the faculty of the HMS PhD program in Biological and Biomedical Sciences. In 2010, he was promoted to Professor of Pathology. He is currently the Chief of the Division of Signal Transduction in the Department of Medicine and the Cancer Center at BIDMC, and also serves as the Associate Director for the BIDMC Cancer Research Institute. He is a member of the Dana Farber/Harvard Cancer Center, and an investigator of the Ludwig Center at Harvard. He is a recipient of an Outstanding Investigator Award from the National Cancer Institute, an elected Fellow of the ASBMB, President-elect of the American Association of University Pathologists, and a recipient of the 2022 Avanti Award in Lipids (ASBMB). He is also the Editor-in-Chief of the Journal of Biological Chemistry (JBC).

For over 25 years, Dr. Toker’s research has focused on signal transduction mechanisms in normal and malignant cells. In the mid-1990s, he discovered the mechanism by which phosphoinositide 3-kinase transduces signals to the protein kinase effector AKT/PKB, and has since maintained an active interest in AKT regulation and function, with special emphasis in breast cancer. His group was the first to discover specific functions of AKT isoforms in breast cancer and has also identified a number of specific substrates that transduce the AKT signal in phenotypes associated with malignancy. More recently his group has been investigating the reprogramming of metabolic pathways by aberrant PI3K and AKT signaling in human cancers and has also uncovered mechanisms that mediate resistance to both small molecule inhibitors under clinical development, as well as chemotherapeutic agents that are standard-of-care in the clinic. The goal of his laboratory is to decipher the complex mechanisms by which these pathways impact cancer progression, with the ultimate goal of developing drugs to interfere with malignancy and metastasis.