PHILADELPHIA (February 25, 2025) — Researchers at Fox Chase Cancer Center recently published two reviews on the complex role of AKT, also known as protein kinase B, in the development and treatment of cancer.
AKT regulates numerous functions in normal cells, including survival, proliferation, growth, cell death, and glycogen metabolism, so its activity may affect every cell in the body. However, when AKT goes haywire, it can cause tumor initiation, disease progression, and resistance to anticancer therapies, so many clinical trials have been initiated using small-molecule inhibitors to target the AKT pathway.
The protein was first shown to play a role in malignancy in a highly cited 1991 Fox Chase study that is considered the starting point for a plethora of research that significantly impacted the cancer field. The study, which focused on AKT as a retroviral oncoprotein and novel signaling kinase, was published in Science.
That research was conducted by Alfonso Bellacosa, MD, PhD, at the time a postdoctoral fellow in the laboratory of Philip Tsichlis, MD, then a senior researcher at Fox Chase, and Joseph Testa, PhD, Professor and Carol & Ken Weg Chair in Human Genetics at Fox Chase, who brought the AKT project to Fox Chase when he joined it in 1989.
Bellacosa is now a Professor at Fox Chase, and Tsichlis is Professor and former Chair of the Department of Cancer Biology and Genetics at the Ohio State University. Stephen Staal, MD, now an oncologist with University of Florida Health, was also a co-author of the Science publication, having isolated the AKT retrovirus and cloned small fragments of the oncogene transduced by the virus.
A follow-up landmark paper from Tsichlis’ lab published in Cell in 1995, during his tenure at Fox Chase, placed AKT in the center of the PI3K pathway, one of the main pathways controlling cellular and organismal physiology. The deregulation of this pathway plays a critical role in cancer.
A highly cited 1992 publication in the Proceedings of the National Academy of Sciences by the Testa lab, in collaboration with the Tsichlis group and former Fox Chase faculty member Andrew Godwin, PhD, now an endowed professor and cancer center Deputy Director at the University of Kansas Medical Center, described alterations of AKT in ovarian cancer. It was the first of many such publications linking AKT to human cancer and identifying AKT and other molecules in the PI3K/AKT pathway as important targets for cancer treatment.
Testa and Bellacosa believe that promise has finally been realized. In one of the new reviews, Bellacosa and co-authors discuss AKT inhibitors and their therapeutic significance, including in combination with immunotherapies. Bellacosa worked on the review with Testa, Dalal Hassan, BMBCh, MS, a visiting scientist in Bellacosa’s lab, and Craig Menges, PhD, who previously worked with Testa and is now at Eurofins Scientific focusing on CAR-T cell therapy.
The authors discuss how AKT serves as a central node for a signaling pathway pivotal for a range of normal cellular functions and several pathological conditions, including cancer, inflammatory and autoimmune diseases, and overgrowth syndromes.
“There was no doubt that this protein was relevant for cancer and various other processes. However, we lacked evidence that blocking the AKT pathway would have clinical benefit,” said Bellacosa. “Excitingly, research published just a few months ago showed that AKT inhibitors have a positive effect in patients with triple-negative breast cancer.”
Testa and Eleonora Sementino, MS, a senior technologist in his lab, spearheaded the second article, an overview of AKT’s central role in cancer, with Bellacosa and Hassan as co-authors. It was prompted by earlier research outlining the fundamental hallmarks of cancer biology initially proposed by Douglas Hanahan, PhD, Distinguished Scholar at the Ludwig Institute for Cancer Research, and Robert Weinberg, PhD, the Daniel K. Ludwig Professor for Cancer Research at the Massachusetts Institute of Technology.
What began as six cancer hallmarks in 2000 eventually developed into 14 by 2022. These include characteristics such as the ability of cancer cells to proliferate without regulation and to survive and develop resistance to traditional anticancer drugs.
“Recently, it has become increasingly clear that the AKT pathway plays a critical role in many aspects of cancer. Upon looking deeper, we discovered that AKT is involved in all 14 cancer hallmarks. Moreover, given AKT’s frequent involvement in many types of cancer, there is now enormous interest in targeting the AKT pathway as a rational therapeutic strategy,” Testa said.
“Little did I know nearly four decades ago, when Steve Staal asked me to map a human AKT1 fragment, that its protein product would be so important. Now there are more than 130,000 publications on AKT, nearly 65,000 of which are directly related to cancer, so we thought this would be an ideal time to reflect on the AKT pathway’s biological and clinical importance in malignancy. It’s timely because investigators are now finding innovative ways to specifically target mutant forms of AKT in a clinically efficacious manner,” he added.
“These new mutant-selective inhibitors are expected to dramatically improve the treatment of cancers fueled by mutant AKT alleles while having only minimal side effects on glucose homeostasis,” Bellacosa said.
Bellacosa’s review, “AKT Kinases as Therapeutic Targets,” was published in the Journal of Experimental and Clinical Cancer Research. Testa’s review, “AKT and the Hallmarks of Cancer,” was published in Cancer Research.