Targeting a super-enhancer induced aldehyde dehydrogenase metabolic loop mitigates CDK4/6 inhibitor resistance in estrogen receptor-positive cancers.

CDK4/6 inhibitors (CDK4/6i) have shown striking clinical potential in hormone receptor-positive breast cancers (BC) and endometrial cancers (EC), whereas resistance hinders their clinical utilization. The role of epigenetic alterations in CDK4/6i resistance remains poorly elucidated. Herein, through a comprehensive analysis of transcriptomic and chromatin profiles in 16 EC tissues and cell-based resistance models, we delineate the super-enhancer (SE) landscape and identify aldehyde dehydrogenase 1 family member A1 (ALDH1A1) as a SE-driven gene closely associated with CDK4/6i resistance. ALDH1A1 inhibition increases susceptibility to CDK4/6i in multiple EC and BC models. Mechanistically, we demonstrate that ALDH1A1 promotes vitamin A (vitA) metabolism and induces the accumulation of its downstream metabolite, retinoic acid (RA), in resistant cells. In return, the elevated RA potentiates the interaction between retinoic acid receptor alpha (RARα) and estrogen receptor alpha (ERα) in the nucleus and facilitates RARα/ERα-occupied SE-driven transcriptional activation of ALDH1A1, establishing a positive feedback loop that promotes CDK4/6i resistance. These findings highlight the crucial role of vitA metabolism in the epigenetic transcriptional program associated with CDK4/6i resistance, suggesting that avoiding high vitA intake or inhibiting the ALDH1A1-RA axis may be effective strategies to overcome this challenge.