Researchers have found that a DNA repair–facilitating mechanism may be responsible for a tumor’s treatment resistance and could be treated with a combination of chemotherapies, according to a recent study published by Marullo et al in Cancer Research. The mechanism involves the shuttling of messenger RNA (mRNA) from the nucleus to the cytoplasm, which facilitates DNA repair in cancer cells and thereby allows the cancer cells to thwart treatments aimed at damaging their DNA.
Background
Diffuse large B-cell lymphoma (DLBCL)—the most common form of lymphoma, affecting about 30,000 U.S. patients per year—can be cured with first-line therapies in about two-thirds of patients.
“[However], for [patients] who aren’t cured or who relapse, they historically had poor outcomes with standard chemotherapy-based treatment approaches,” explained co–lead study author Sarah Rutherford, MD, Assistant Professor of Medicine and a member of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine as well as a hematologist/oncologist at NewYork-Presbyterian/Weill Cornell Medical Center.
Previous studies have found that treatment-resistant DLBCL cells often express high levels of the protein XPO1. The protein transports hundreds of proteins and certain RNAs out of the cell nucleus, primarily to separate the pool of proteins that should not be present in the nucleus, such as ribosomal proteins.
In 2019, the U.S. Food and Drug Administration approved the drug selinexor—designed to hinder the growth of lymphoma cells expressing high levels of XPO1—to target the protein and inhibit its activity in refractory cases. Selinexor has helped many but not all patients with treatment-resistant disease.
“Selinexor is effective by itself; it’s just not as effective as we’d like it to be,” stressed Dr. Rutherford.
Study Methods and Results
In the new study, the researchers examined how selinexor worked and sought new strategies to improve the efficacy of the drug in patients with DLBCL. They demonstrated that some of the XPO1-exported proteins were also bound to mRNA molecules; thus, these mRNAs were exported out of the cell nucleus into the cytoplasm, where they could be translated into proteins. This new mechanism indicated that the quantity and activity of XPO1 in a cell may affect the expression levels of numerous genes.
“We found that it’s not just regulating a few proteins, it’s coordinating these big programs, allowing cells to rapidly adjust their proteome and survive different kinds of stress that cancer cells encounter all the time,” detailed senior study author Leandro Cerchietti, MD, the Richard Stratton Associate Professor of Hematology and Oncology as well as a member of the Meyer Cancer Center at Weill Cornell Medicine.
Taking some treatment-resistant DLBCL cells from the patients and grafting them into preclinical models, the researchers discovered that higher levels of XPO1 ultimately increased the expression of genes protecting the cells against death from DNA damage. Inhibiting XPO1 in those models with selinexor increased the lymphomas’ sensitivity to DNA-damaging chemotherapies and immune-based treatments.
“We were excited, and based on some of Dr. Cerchietti’s research, we thought selinexor would likely synergize with other chemotherapies,” said Dr. Rutherford.
To test that in patients, she and her colleagues initiated a phase I clinical trial with the goal of assessing whether such a combination would be safe and, if so, at what doses. The researchers primarily enrolled patients with treatment-resistant DLBCL and showed that the combined regimen was safe and effective. They reported that several of the patients experienced better outcomes than expected; however, the data set was too small to draw definitive conclusions.
Conclusions
Because every cell in the body expresses XPO1, the new results may have broader applications. The researchers noted that although their research focused on DLBCL, the new findings likely apply to other cancer types as well. They hope to further test and refine the new regimens in follow-up trials.
“It has been a really exceptional time over the last 4 years or so in this disease, where we now have many more therapies than we did when we first started the trial,” Dr. Rutherford underscored.
“There are other tumors in which XPO1 is overexpressed, so it’s really a nice backbone to build on,” concluded Dr. Cerchietti.
Disclosure: For full disclosures of the study authors, visit aacrjournals.org.
