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AACR 2023: Strategies to Overcome Resistance to Chemotherapy in Patients With Myeloma

By: Joshua Swore, PhD
Posted: Friday, April 21, 2023

Research presented at the American Association for Cancer Research (AACR) Annual Meeting 2023 (Abstract 452/16) highlights the potential of targeting ULK3, a key regulator of autophagy, in patients with refractory multiple myeloma using novel inhibitors SG3014/MA9060 to resensitize the disease to standard proapoptotic therapy.

“Classical chemotherapeutics including bortezomib, melphalan, lenalidomide, and thalidomide have greatly enhanced survival times. Unfortunately, patients typically relapse and become refractory, with an average survival of 5 years post-diagnosis,” said Marilena Tauro, PhD, of the Moffitt Cancer Center, Tampa, Florida. “Our emerging studies demonstrate a novel role for ULK3 in regulating autophagy in [multiple myeloma], a key program that sustains cell survival under times of stress and has been implicated as a major mechanism of proteasome inhibitor resistance.”

The study used RNA sequencing of CD138-positive multiple myeloma cells from 815 patients with varying degrees of disease to identify the role of ULK3 in disease progression and resistance to chemotherapy. The researchers used genetic ablation of ULK3 by small interfering RNA in cell lines, immunoblotting to measure protein expression levels, and in vivo preclinical models to test the efficacy of the inhibitors.

The researchers found that expression of ULK3 was significantly correlated with the stage of multiple myeloma. Patients with refractory multiple myeloma and drug-resistant cell lines possessed higher expression of ULK3. When ULK3 was genetically ablated, the authors observed a rapid decrease in the downstream autophagy and cell death within 72 hours of transduction. Immunoblotting of cells treated with ULK3 inhibitors revealed a progressive decrease in ULK3 levels. Finally, the authors reported that use of ULK3 inhibitors in in vivo preclinical models demonstrated efficacy in reducing tumors and extending overall survival (65 days vs. 110 days).

“Our dual inhibitors can increase overall survival in vivo and ex vivo; therefore, we expect to quickly translate our novel molecules to the clinic,” the investigators concluded.

Disclosure: The study authors reported no conflicts of interest.

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