Weizmann study identifies genes connected to myeloma drug resistance

The Weizmann team found that they could silence one of the genes responsible for drug resistance to help make drugs more effective.

Resistant multiple myeloma cells (violet-blue) in two samples, seen under a microscope (photo credit: WEIZMANN INSTITUTE OF SCIENCE)
Resistant multiple myeloma cells (violet-blue) in two samples, seen under a microscope
Researchers from the Weizmann Institute of Science and the Tel Aviv Sourasky Medical Center have found 30 genes that seem to be responsible for the resistance that multiple myeloma shows to treatment, which may help lead to more informed, personalized treatment for patients.
Malignant myeloma is a cancer of the antibody-producing plasma cells in bone marrow. Most patients develop resistance to medications and in some, the cancer is resistant to therapy from the start.
The study, published in Nature Medicine last week, examined newly diagnosed myeloma patients at Sourasky and 14 other hospitals whose cancers had failed to respond to initial therapy or relapsed soon afterwards.
The patients were enrolled in a clinical trial aimed at testing whether a combination of four anti-myeloma drugs could overcome the cancer's resistance.
While the physicians evaluated the success and safety of the treatment, the Weizmann scientists worked to figure out what genetic changes had occurred in the cancers to make them resistant to the drugs. Samples of bone marrow were taken from the patients before, at various stages during and after the therapy and analyzed with singe-cell RNA sequencing.
Single-cell RNA sequencing creates high-resolution genetic profiles of thousands of individual cells simultaneously, allowing researchers to analyze genetic makeup at an extremely high level of detail.
"What's unique about this technology is that it helps distinguish between different types of cancer cells in the same patient, whereas standard hospital techniques examine all those cells together, including the healthy plasma cells, in bulk," said Dr. Assaf Weiner, a member of the Weizmann team. "These different cell types may respond differently to treatment, so obtaining a complete cellular and molecular profile of the cancer is crucial to understanding why a certain treatment might not work, or why some tumor cells may develop resistance."
DETAILED PROFILES of tens of thousands of bone marrow cells were collected from each of the 41 patients in the trial. The profiles were then compared with profiles from healthy people and newly diagnosed multiple myeloma patients without primary treatment resistance.
The Weizmann researchers were able to identify 30 genes that seem to make up a genetic signature of resistance.
"We found that these genes belonged to genetic pathways responsible for protein folding and degradation, and for cellular response to stress," explained Dr. Shuang-Yin Wang, a member of the Weizmann team.
In nearly half of the resistant patients, these genetic pathways were abnormally active, apparently enabling the cancer to escape the effects of the drugs. The proteasome inhibitors used for treatment shut down the cellular machinery and end up killing the malignant cell. The pathway found by the researchers helps the malignant cells fold their proteins more efficiently, preventing jamming and limiting the effects of the drugs.
About five percent of all newly diagnosed patients have this genetic signature, but the prevalence of the signature increased dramatically in patients whose disease had progressed after receiving several lines of treatments. This is expected, according to the researchers, as most patients develop resistance to therapy.
The patients with the genetic signature in the trial responded poorly to the combination therapy. 
The Weizmann team found that they could block the protein folding genetic pathway by silencing one of its key genes, called PPIA.
“When we deleted this gene from the genome of multiple myeloma cells using CRISPR gene editing technology, we found that the modified cells were vastly more sensitive to anti-myeloma proteasome inhibitor drugs,” said Mor Zada, a member of the Weizmann team.
The cancer cells were exposed to a drug called Cyclosporin A, which neutralizes the activity of the PPIA; researchers then added the anti-myeloma proteasome inhibitor drug generally used in treatment. The drug was much more effective when applied with Cyclosporin A than without.
A clinical trial is still required to test whether Cyclosporin A can help treat patients with resistant multiple myeloma.
"This research can serve as a roadmap for integrating single-cell sequencing into other clinical trials – enabling physicians to treat patients with drugs that are best suited to their disease and also finding new molecular targets for the development of more effective treatments," said Prof. Ido Amit of Weizmann's Immunology Department.