Repurposing a Drug Used for Alcohol Abuse May Overcome MM Treatment Resistance

Researchers of a new study are proposing a potential solution to overcoming resistance to standard-of-care treatment for multiple myeloma (MM): a drug used for alcohol abuse.

While effect of disulfiram (DSF) alone on cancer cells has been studied previously, recent research has refuted the hypothesis that DSF’s anticancer effect is related to inhibition of aldehyde dehydrogenase. According to these new findings from MM cell lines, metabolizing DSF into diethyldithiocarbamate-copper complex (CuET) creates a proteasome inhibitor (PI)-like treatment that enables the efficient killing of treatment-resistant MM cells.

“Altogether, our data suggest that DSF, particularly when combined with copper, is a candidate for an attractive and readily available treatment option for patients with relapsed and/or therapy-resistant MM,” described the group.

“Gaps in our knowledge about the pharmacokinetics of CuET formation in patients, interference with other medications and the lack of predictive biomarkers currently preclude a wider application of DSF in oncology. On the other hand, some of the outstanding questions will hopefully be answered by the currently ongoing clinical trials with DSF repurposing in treatment of solid human malignancies, thereby also paving the way for use in therapy-refractory MM patients.”

Similar to findings seen with bortezomib (BTZ) and other PIs, exposure to CuET resulted in the accumulation of polyubiquitinated proteins (poly-Ubs) and activation of UPR and HSR. However, the researchers also made unique observations with CuET, including enrichment of insoluble poly-Ub proteins and activation of HSP70.

Assessed in BTZ-resistant MM mutated in PSMB5, the mutation attributed to BTZ resistance as well as resistance to second-generation PIs, CuET was able to demonstrate efficacy against MM despite the mutation. According to the researchers, this is similar to p97 inhibitor CB5083.

“An important question raised from our data is why CuET is even more efficient in these resistant models than p97 inhibitors. We speculate that this might involve the triggering of additional toxic effects induced by CuET,” wrote the researchers. “Upon CuET treatment, NPL4 protein forms aggregates, which leads not only to impairment of protein degradation and p97 function but also activates massive HSR. Activated HSR by itself might contribute to the toxic effects in MM cells as suggested in a recent report. Under treatment with CuET, the HSR is activated by NPL4 protein aggregates which can sequester and immobilize various other proteins including the ATR kinase, with consequences for replication stress and DNA damage.”

Notably, the data also showed that CuET could be effective regardless of disease stage and resistance status and the treatment’s cytotoxic effect was targeted more favorably toward tumor cells. Among 14 samples of MM, including those that were newly diagnosed, currently receiving treatment, and resistant/relapsed, the amount of MM cells were significantly decreased after CuET treatment. Effectiveness was confirmed in MM cells of patients who were resistant and/or relapsed following previous treatment with drugs used in clinical practice.

Reference

Chroma K, Skrott Z, Gursky, et al. A drug repurposing strategy for overcoming human multiple myeloma resistance to standard-of-care treatment. Cell Death Dis. 2022;13(3):203. doi: 10.1002/cam4.4692