Promoter reinforcement supports transcriptional resilience in drug-resistant cancer.

In mammalian cells, gene-distal regulatory elements enable long-range gene regulation and support cell-type-specific transcriptional programs. This regulatory architecture is frequently perturbed in cancer, particularly when oncogenic transcription factors are targeted therapeutically. However, how cancer cells adapt under such selective pressure has remained poorly understood. Here we show that mesothelioma cells dependent on the oncogenic TEAD family of transcription factors acquire resistance to a pan-TEAD inhibitor. Such resistance is accompanied by a promoter-centric regulatory mechanism, a process we term promoter reinforcement, to sustain gene expression following TEAD inhibition. Using base-pair-resolution Micro Capture-C on a set of TEAD target genes, we find that regulatory element-promoter interactions are weakened or lost in resistant cells, even as promoter activity and gene expression recover in the context of partial epigenetic restoration. Mechanistically, resistance-induced transcription factors show promoter-biased localization and can increase promoter activity, whereas distal regulatory element function can become dispensable. Together, these findings identify promoter reinforcement as a locus-specific compensatory response that supports transcriptional resilience under TEAD inhibition, indicating promoter-associated vulnerabilities in drug-resistant cancer.