Inter- and intra-tumoral ALDH1 heterogeneity in breast cancer identifies therapeutic opportunities for ALDH1A-specific inhibitors

Basal-like breast Cancer is an aggressive subtype with limited therapeutic options. Here, transcriptomic analysis of public datasets suggested distinct subtype- and cell-specific expression patterns of ALDH1A isoforms in breast tumors, with ALDH1A3 predominantly expressed in the epithelial cells of basal-like tumors, whereas ALDH1A2 and ALDH1A1 were enriched in stromal and immune-associated subpopulations. High expression of ALDH1A3 and ALDH1A2, but not ALDH1A1, is associated with poor prognosis in high-grade, lymph-node-positive tumors. To evaluate therapeutic targeting, we developed ABD0171, an irreversible, selective ALDH1A3 inhibitor with additional ALDH1A1 activity. ABD0171 disrupted key oncogenic pathways, including IL6/JAK/STAT3, tPA, and Src/FAK, resulting in robust antitumor and antimetastatic effects in vitro and in vivo, with a favorable safety profile. These findings establish ALDH1A3 as a therapeutic target in breast cancers with epithelial-basal traits and validate ABD0171 as a promising clinical candidate to address current treatment challenges.