K. A. L. Vu, S. Moein, K. Kumari, B. H. Liu, C. Gao, M. Liu, M.-Y. Dai, Z. Liu, F. Li, J. Tang, D. Maddalo, D. Auld, D. Casalena, X. Tian, M. A. Bassal, V. Iakovleva, M. K. Jayasinghe, J. Tan, a. stein, C. Budjan, C. X. Shao, Q. Zhou, P. Fischer, L. Sigua, J. Qi, H. Arthanari, G. Wulf, D. Tenen, L. Chai
Immunomodulatory (IMiD) drugs have shown prominent therapeutic activity in hematologic malignancies; however, their use in solid tumors is limited. The oncofetal protein SALL4 is essential for cancer cell survival. While IMiDs can induce SALL4 degradation, they fail to induce cell death in SALL4-expressing cancer cell lines. Here, we observed that this inefficacy arose from their selective degradation of the long SALL4 isoform while sparing the short SALL4B isoform. Selective silencing of SALL4B phenocopied total SALL4 depletion by inducing cancer apoptosis, underscoring the critical role of SALL4B in cancer maintenance. Recognizing that IMiDs cannot degrade SALL4B, we performed a high-throughput screen to identify compounds capable of achieving this effect. We identified a small-molecule compound that degrades both SALL4 isoforms, with enhanced potency toward SALL4B, in a cereblon- and proteasome-dependent manner. This compound suppressed cancer cell proliferation and attenuated tumor development in both cell line-derived and patient-derived xenograft models. Transcriptomic analyses further revealed convergent effects of genetic and pharmacologic SALL4B depletion on DNA damage response and replication pathways. Together, these findings identify SALL4B as the therapeutically relevant isoform in SALL4-dependent cancers and establish isoform-aware targeted degradation as a strategy to overcome the limitations of IMiDs in solid tumors.