Researchers at the University of British Columbia Medical School and the BC Cancer Research Institute have uncovered a weakness in a key enzyme that solid cancer cells in tumors depend on to adapt and survive when oxygen levels are low.
The findings, published August 27, 2021
Solid tumors rely on blood supply to supply oxygen and nutrients to help them grow. As the tumors progress, these blood vessels are unable to provide oxygen and nutrients to all parts of the tumor, resulting in areas with low oxygen. Over time, this low-oxygen environment leads to an accumulation of
“> acid inside the tumor cells.
To overcome this stress, the cells adapt by releasing enzymes that neutralize the acidic conditions in the environment, so that the cells can not only survive, but eventually become a more aggressive form of tumor that can spread to other organs. One of these enzymes is called carbonic anhydrase IX (CAIX).
Cancer cells depend on the CAIX enzyme to survive, which ultimately makes them their “Achilles’ heel”. By inhibiting the activity, we can effectively stop the cells from growing, ”explains the study’s senior author Dr. Shoukat Dedhar, professor at the UBC Faculty of Medicine Department of Biochemistry and Molecular Biology and prominent researcher at BC Cancer.
Dr. Dedhar and colleagues previously identified a unique compound, known as SLC-0111 – which is currently being evaluated in Phase 1 clinical trials – as a potent inhibitor of the CAIX enzyme. Although preclinical cancer models of breast, pancreatic and brain cancer have shown the effect of this compound in suppressing tumor growth and spread, other cellular properties reduce its effectiveness.
In this study, the research team, which included Dr. Shawn Chafe, a research assistant in Dr. Dedhar’s laboratory, together with Dr. Franco Vizeacoumar and colleagues from the University of Saskatchewan, sat down to investigate these cellular properties and identify other weaknesses of the CAIX enzyme. using a powerful tool known as a genome-wide synthetic lethal screen. This tool looks at the genetics of a cancer cell and systematically deletes one gene at a time to determine if a cancer cell can be killed by eliminating the CAIX enzyme along with another specific gene.
According to Dr. Dedhar, the results of the study were surprising and point to 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 tumor’s metabolism and cell membranes.
“We now know that the CAIX enzyme blocks cancer cells from dying from ferroptosis,” says Dr. Dedhar. “Combining CAIX inhibitors, including SLC-0111, with compounds known to cause ferroptosis, results in catastrophic cell death and inhibits tumor growth.”
A major international effort is currently underway to identify drugs that can cause ferroptosis. This study is a major step forward in this quest.
Reference: “Genome-wide synthetic lethal screen reveals new CAIX-NFS1 / xCT axis as a measurable 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, 27 August 2021, Scientific advances.
DOI: 10.1126 / sciadv.abj0364