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

Despite the availability of effective therapies such as proteasome inhibitors, multiple myeloma (MM) patients relapse with refractory disease. To identify new therapeutic targets, we assessed RNA sequencing data from CD138(+) MM patient cells (n = 813) across disease stages and found that an autophagy gene signature, and particularly ULK3 expression, was strongly associated with disease progression. Functional studies revealed that ULK3 contributes to MM cell survival as part of the ULK-ATG13-FIP200 complex. We generated inhibitors (SG3-014/MA9-060) with nanomolar potency and confirmed their binding mode through co-crystallization with ULK3. In vivo, ULK3 inhibition reduced MM burden, improved survival, and protected against cancer-induced bone disease. MA9-060 also restored sensitivity to proteasome inhibitors in resistant MM cells. This synergy was validated ex vivo in patient samples, especially those with high ULK3 expression. 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.