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Treatment-resistant cancers have Achilles’ heel

Common vulnerability is druggable pathway leading to iron-induced cell death

by Stu Borman
July 14, 2017 | A version of this story appeared in Volume 95, Issue 29

Photo of Schreiber and coworker Vasanthi S. Viswanathan.
Credit: John K. Eaton
Schreiber (left) and Vasanthi S. Viswanathan, first author of the new paper, in their Broad Institute lab.

Through mutations or changes in gene expression patterns, some cancer cells become resistant to common treatments such as radiation, chemotherapy, targeted drug therapy, and immunotherapy.

El ML210 es uno de los diferentes compuestos que inhibe GPX4, una enzima que protege a las células cancerosas resistentes al tratamiento de la muerte celular.
Chemical line structure of GPX4 inhibitor ML210.
ML210 is one of several compounds that inhibit GPX4, an enzyme that protects treatment-resistant cancer cells from cell death.

A new study reports that these resistant cancers do have a vulnerability: They depend on an enzyme to protect them from iron-produced free radicals (Nature 2017, DOI: 10.1038/nature23007). The work opens a potential new route to fight cancer in people who currently lack good treatment options because conventional ones don’t work, say the researchers, led by Stuart L. Schreiber of Broad Institute and Harvard University.

Often cancer cells become resistant to therapies because of genetic mutations. But the new study focused instead on mesenchymal cancer cells, which gain resistance through changes in gene expression. The researchers believe this type of gene-expression “plasticity” to be an initial response of cancer cells to treatment, after which the cells can go on to make mutational changes as well.

The team screened a library of small molecules to look for compounds that could break the cells’ armor. The screening experiments revealed that the cells have an unusually high susceptibility to ferroptosis, a recently discovered form of self-induced cell death in which iron catalyzes the formation of free radicals that kill the cells.

In particular, the researchers found molecules that kill mesenchymal cancer cells by inhibiting a selenoenzyme called glutathione peroxidase 4 (GPX4). Mesenchymal cancer cells oxidize polyunsaturated lipids to form lipid peroxides. Iron in the cells can react with the excess lipid peroxides to produce lipid radicals that cause ferroptosis. To protect the cells from ferroptosis, GPX4 reduces the lipid peroxides to lipid alcohols.

Schematic shows two resistant-cancer cell pathways—one leading to ferroptosis and one controlled by GPX4, which inhibits ferroptosis.
Credit: Adapted from Nature
Therapy-resistant cancer cells oxidize polyunsaturated lipids to form lipid peroxides. Iron can react with the peroxides to produce lipid radicals that poison the cells, causing ferroptosis. But GPX4 reduces the lipid peroxides, protecting the cells from ferroptosis. Agents such as ML210, which block GPX4, exploit the cells’ susceptibility to ferroptosis and allow the cells to kill themselves.

GPX4 inhibitors block this protective pathway and use the cells’ susceptibility to ferroptosis to let them kill themselves. In cell culture and mice experiments, several GPX4 inhibitors from the team’s compound library killed treatment-resistant cancers, including non-small cell lung cancer, pancreatic cancer, prostate cancer, and melanoma.

Schreiber describes the work as “a chemical biology-based approach to understanding resistance.” The study’s key insights, he says, “were gained by seeing a bizarre pattern of sensitivity of 900 cancer cell lines to 500 selective small-molecule probes.” To help cancer researchers find other vulnerabilities in cancer cells and accelerate therapeutic discoveries, the team has made its screening data and analysis tools freely available at an online resource called the Cancer Therapeutics Response Portal.

Arjun Raj of the University of Pennsylvania, who has studied treatment-resistant cancers, calls the work very important. “One of the most exciting findings is that treatment-resistant cancer cells have some convergent general principles that can be exploited therapeutically, instead of the case-by-case, whack-a-mole approach that is currently dominant” for treating resistant cancers, he says. “Identifying the GPX4 pathway raises many exciting therapeutic possibilities.”

This article has been translated into Spanish by and can be found here.



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