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    Myeloma Novel Drug Targets and agents

    Category: Myeloma Novel Drug Targets and agents

    Unc-51 Like Kinase 3 (ULK3) is essential for autophagy and cell survival in multiple myeloma.

    (PA-320) Unc-51 Like Kinase 3 (ULK3) is Essential for Autophagy and Cell Survival in Multiple Myeloma

    Wednesday, September 17, 2025
    Introduction: Despite the availability of effective therapies, multiple myeloma (MM) patients often relapse with refractory disease.

    Methods: To identify novel targets that drive this skeletal malignancy, we assessed RNA sequencing data performed on CD138+ MM patient cells (n = 813) with premalignant, newly diagnosed, and relapsed/refractory disease. These analyses revealed a significant correlation between an autophagy gene signature and MM progression. While basal rates of autophagy are known to be high in MM, Unc-51 Like Kinase 3 (ULK3) significantly correlated with disease progression.

    Results: Here, we report a role for ULK3 as part of a ULK-ATG13-FIP200 effector complex in controlling autophagy and MM cell survival. Further, we generated multi-kinase inhibitors (SG3-014/MA9-060) that block ULK3 enzymatic activity in the nanomolar range and co-crystalized the MA9-060: ULK3 complex to reveal its molecular binding mode. In vivo, ULK3 blockade significantly reduced MM burden, improved overall survival, and protected against cancer-induced bone disease. Furthermore, MM cells resistant to proteasome inhibitors (PI) can be resensitized to PI by co-treatment with MA9-060. Importantly, these findings were validated with specimens from newly diagnosed and refractory MM patients. In fact, potent synergy was observed with MA9-060/PI combination in specimens expressing high levels of ULK3.

    Conclusions:

    Collectively, these findings indicate a new role for ULK3-mediated autophagy in cancer and suggest that ULK3 inhibition is an effective treatment strategy for both newly diagnosed and refractory MM disease.