Vulnerability Found in Solid Tumours
Researchers have found a weakness in a key enzyme key for solid tumour cancer cells’ ability to adapt and survive when oxygen levels are low.
The findings, published in Science Advances, will help researchers develop new treatment strategies to limit the progression of solid cancer tumours, which represent the majority of tumour types that arise in the body.
As tumours advance, the blood vessels that they previously relied on become unable to provide oxygen and nutrients to all parts of the tumour, which results in areas of hypoxia. Over time, this hypoxic environment leads to a buildup of acid inside the tumour cells.
To overcome this stress, the tumour cells adapt by releasing enzymes that neutralise the acidic conditions of their environment, enabling the cells to not only survive, but develop into a more aggressive form of tumour capable of spreading 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 it their ‘Achilles heel.’ By inhibiting its activity, we can effectively stop the cells from growing,” explained senior author Dr Shoukat Dedhar, professor in UBC faculty of medicine’s department of biochemistry and molecular biology and distinguished scientist at BC Cancer.
Previously, Dr Dedhar and colleagues had identified a unique compound, known as SLC-0111 (which is currently being evaluated in Phase 1 clinical trials) as a powerful CAIX enzyme inhibitor. Though the effectiveness of this compound in suppressing tumour growth and spread has been tested in pre-clinical models, other cellular properties diminish its effectiveness.
In this study, the researchers set out to investiagete these cellular properties and identify other weaknesses of the CAIX enzyme with the help of a powerful tool known as a genome-wide synthetic lethal screen. This tool systematically deletes one gene at a time from a cancer cell’s genome to determine if a cancer cell can be killed by eliminating the CAIX enzyme together with another specific gene.
According to Dr Dedhar, they had surprising results and point to an unexpected role of proteins and processes that control a form of cell death called ferroptosis, a form of cell death that occurs from an iron build up which weakens the tumour’s metabolism and cell membranes.
“We now know that the CAIX enzyme blocks cancer cells from dying as a result of ferroptosis,” said Dr Dedhar. “Combining inhibitors of CAIX, including SLC-0111, with compounds known to bring about ferroptosis results in catastrophic cell death and debilitates tumour growth.”
The development of drugs to induce ferroptosis is underway around the world, and this study is contributing to their work.
Source: University of British Columbia
