A protein that can dial down oxidative stress in cells helps some cancers resist treatment with a widely used class of drugs called BTK inhibitors, according to a study led by investigators at Weill Cornell Medicine. The discovery points to a possible solution to the problem of BTK inhibitor treatment resistance.
BTK inhibitors reduce the activity of the enzyme BTK (Bruton's tyrosine kinase), which has a central role in immune cells called B cells. Inhibiting BTK chokes off the ability of B cells to proliferate, which has benefits against some blood cancers including several types of lymphoma. Unfortunately, these malignancies often lose their sensitivity to BTK inhibitors after a year or two of treatment.
In the study, published July 2 in Nature Communications, the researchers discovered that in mantle cell lymphoma, a common mechanism of resistance to BTK inhibitors involves aberrant activity of the protein BRG1. They found that BRG1 protects cells from BTK-inhibitor treatment by suppressing ferroptosis, an iron-dependent form of cell death that BTK inhibitors otherwise induce.
"These findings reveal a potential new therapeutic vulnerability that could be targeted to overcome drug resistance and extend the benefit of BTK inhibitors for patients with B-cell cancers," said study co-senior author Jihye Paik, associate professor of pathology and laboratory medicine and a member of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine.
The study was led by first author Soo-Yeon Hwang, a postdoctoral associate in the Paik Lab, together with co-senior author Hongwu Zheng, assistant professor of research in pathology and laboratory medicine at Weill Cornell Medicine.
Ferroptosis, discovered in 2012, involves the runaway, iron-catalyzed oxidation of lipid molecules that make up the cell membrane, resulting in membrane rupture and cell death. Cells become more vulnerable to ferroptosis when they are dividing rapidly, as malignant cells do, and researchers have been finding that many different types of cancer treatment work by triggering this mechanism.
In the study, Hwang and colleagues found that in lymphoma cells sampled from mantle cell patients who responded to BTK inhibitors, treatment kills cells by inducing ferroptosis. In contrast, BTK inhibitor treatment fails to induce ferroptosis in cells from patients who had stopped responding to the drugs. The researchers traced this resistance effect to aberrant BRG1, which is frequently mutated in resistant mantle cell lymphoma. They showed that BRG1 helps prevent ferroptosis by reducing the presence of its main ingredients: reactive oxygen and free iron molecules.
"We found that the chromatin remodeler BRG1 rewires gene expression to protect lymphoma cells from ferroptosis, allowing them to survive BTK inhibitor treatment," Hwang said.
Adding an inhibitor of BRG1 markedly improved a BTK inhibitor's antitumor activity and extended survival in animal tests, demonstrating the potential of this strategy in patients with BTK-inhibitor-resistant cancers.
This work was supported in part by the National Cancer Institute, part of the National Institutes of Health; by a Mantle Cell Lymphoma Research Initiative grant from the Leukemia and Lymphoma Society; and by the National Research Foundation of Korea.
Jim Schnabel is a freelance writer for Weill Cornell Medicine.
