Cancer Tumor ‘Achilles Heel’ Research Paves the Way for New Treatment Strategies

Researchers at the University of British Columbia School of Medicine and the BC Cancer Research Institute have found a weakness in a key enzyme that solid tumor cancer cells rely on to adapt and survive when levels of oxygen are low.

The results, published on August 27, 2021, in Scientists progress, will help researchers develop new treatment strategies to limit the progression of solid cancerous tumors, which make up the majority of tumor types that occur in the body.

Solid tumors depend on the blood supply to provide oxygen and nutrients to help them grow. As tumors grow, these blood vessels are unable to deliver oxygen and nutrients to every part of the tumor, resulting in areas of low oxygen content. Over time, this oxygen-poor environment results in a build-up of acid inside tumor cells.

To overcome this stress, cells adapt by releasing enzymes that neutralize acidic conditions in their environment, not only allowing cells to survive, but ultimately to become a more aggressive form of tumor capable of spreading to other organs. . One of these enzymes is called Carbonic Anhydrase IX (CAIX).

Dr Shoukat Dedhar, Professor in the Department of Biochemistry and Molecular Biology at UBC School of Medicine and Distinguished Scientist at BC Cancer. Credit: University of British Columbia

“Cancer cells depend on the enzyme CAIX for survival, which ultimately makes them their ‘Achilles heel.’ By inhibiting its activity, we can effectively prevent cell growth, ”says lead author of the study, Dr. Shoukat Dedhar, professor in the Department of Biochemistry and Molecular Biology at UBC School of Medicine and scientist. honored at BC Cancer.

Dr Dedhar and his colleagues previously identified a unique compound, known as SLC-0111, currently under evaluation in phase 1 clinical trials, as a potent inhibitor of the enzyme CAIX. While preclinical models of breast, pancreatic and brain cancers have demonstrated the efficacy of this compound in suppressing the growth and spread of tumors, other cellular properties decrease its effectiveness.

In this study, the research team, which included Dr. Shawn Chafe, an associate researcher in Dr. Dedhar’s laboratory, as well as Dr. Franco Vizeacoumar and his colleagues at the University of Saskatchewan, set out to examine these cellular properties. and to identify other weaknesses in the CAIX enzyme using a powerful tool known as genome-wide synthetic lethal screening. This tool examines the genetics of a cancer cell and systematically deletes one gene at a time to determine if a cancer cell can be killed by killing the CAIX enzyme along with another specific gene.

According to Dr Dedhar, the results of their examination were surprising and indicate an unexpected role for proteins and processes that control a form of cell death called ferroptosis. This form of cell death occurs when iron builds up and weakens the metabolism and cell membranes of the tumor.

“We now know that the CAIX enzyme prevents cancer cells from dying as a result of ferroptosis,” says Dr Dedhar. “The combination of CAIX inhibitors, including SLC-0111, with compounds known to cause ferroptosis results in catastrophic cell death and weakens tumor growth.”

There is currently a large international effort underway to identify drugs that can induce ferroptosis. This study is a major advance in this quest.

Reference: “Genome-wide Synthetic Lethal Screen Unveils New CAIX-NFS1 / xCT Axis as Target Vulnerability in Hypoxic Solid Tumors” by Shawn C. Chafe, Frederick S. Vizeacoumar, Geetha Venkateswaran, Oksana Nemirovsky , Shannon Awrey, Wells S. Brown, Paul C. McDonald, Fabrizio Carta, Andrew Metcalfe, Joanna M. Karasinska, Ling Huang, Senthil K. Muthuswamy, David F. Schaeffer, Daniel J. Renouf, Claudiu T. Supuran, Franco J . Vizeacoumar and Shoukat Dedhar, August 27, 2021, Scientists progress.
DOI: 10.1126 / sciadv.abj0364