Weill Cornell Medicine and New York-Presbyterian investigators have discovered a surprising mechanism that makes some cancers treatment-resistant. The mechanism, which involves the shuttling of messenger RNAs (mRNAs) from the nucleus to the cytoplasm, ultimately facilitates DNA repair in cancer cells. These cancer cells can thereby fail treatments aimed at damaging their DNA.
In a project that included both basic research and clinical studies, they showed that a combination of approved chemotherapy, including one targeting a DNA repair-facilitating mechanism, could help treat these persistent cases. Work in progress, published in October. 6 inches Cancer researchFocusing on diffuse large B-cell lymphoma (DLBCL), the findings are likely applicable to other cancers as well.
DLBCL is the most common form of lymphoma, affecting approximately 30,000 patients annually in the United States alone. First-line therapies cure about two-thirds of patients, “but for those who are not cured or who relapse, historically there have been poor outcomes with standard chemotherapy-based treatment regimens,” said co-lead author Dr. Sarah Rutherford, an assistant professor of medicine at Weill Cornell Medicine and a hematologist/oncologist at NewYork-Presbyterian/Weill Cornell Medical Center. The other co-lead author is Dr. Rosella Marullo, an instructor of medicine at Weill Cornell Medicine.
Previous studies have shown that treatment-resistant DLBCL cells often express high levels of a protein called XPO1. In 2019, the US Food and Drug Administration approved a new drug, Selinexor, designed to target XPO1 and inhibit its activity. The drug, which inhibits the growth of lymphoma cells that express high levels of the protein, is used to treat these refractory cases. Selinexor has helped many, but not all patients with treatment-resistant disease.
“Selinexor itself is effective, it’s just not as effective as we would like,” Dr. Rutherford, who is also a member of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine. This led him to search for ways to improve the drug’s effectiveness.
Meanwhile, Dr. Rutherford’s colleagues were trying to learn more about how Selinexor works. Its target, XPO1, transports hundreds of proteins and specific RNAs out of the cell nucleus, primarily to sequester a pool of proteins that should not be in the nucleus, such as ribosomal proteins.
However, the investigators found that some of these XPO1-exported proteins also bound to mRNA molecules; Thus, these mRNAs are exported from the cell nucleus to the cytoplasm where they can be translated into proteins. This new mechanism indicates that the amount and activity of XPO1 in a cell can therefore influence the expression levels of numerous genes.
“We found that it’s not just regulating a few proteins, it’s coordinating these larger programs, allowing cells to quickly adjust their proteome and survive the various types of stress that cancer cells are always facing.”
Dr. Leandro Cerchietti, senior author, is the Richard Stratton Associate Professor of Hematology and Oncology and a member of the Meyer Cancer Center at Weill Cornell Medicine.
By taking some treatment-resistant DLBCL cells from patients and grafting them into preclinical models, the researchers found that high levels of XPO1 ultimately increase the expression of genes that protect cells against death from DNA damage. Inhibiting XPO1 in those models with Selinexor increased the sensitivity of lymphomas to DNA-damaging chemotherapy and immune-based treatments.
“We were excited, and based on some of Dr. Cerchitti’s research, we thought Selinexor would probably synergize with other chemotherapy,” said Dr. Rutherford. To test it in patients, he initiated a Phase 1 clinical trial, with the goal of determining whether such a combination is safe, and if so at what dose. The trial, which initially enrolled patients with treatment-resistant DLBCL, shows that the combined approach is not only safe, but appears to work. Although the data set is too small to draw definitive conclusions, several patients had better-than-expected outcomes.
Dr. Rutherford is eager to continue testing and refining the new approach in follow-up trials. “It’s been a really exceptional time over the last four years or so in this disease, where we now have a lot more therapies than when we first started trials,” he said.
Because every cell in the body expresses XPO1, the new findings have the potential for broad applications. “There are other tumors where XPO1 is overexpressed, so it’s a really nice backbone to make,” said Dr. Serchitti
Marullo, R., etc. (2023). XPO1 enables adaptive regulation of mRNA export essential for genotoxic stress tolerance in cancer cells. Cancer research. doi.org/10.1158/0008-5472.can-23-1992.