Abstract Endocrine therapy resistance (ETR) in estrogen receptor-positive breast cancer arises through multiple adaptive mechanisms, with kinase reprogramming representing a central driver of therapeutic escape. N6-methyladenosine (m6A), the most abundant internal RNA modification, has emerged as a key regulator of RNA fate, yet its role in restructuring kinase networks during ETR is unclear. Using GLORI sequencing, a single-nucleotide-resolution method for stoichiometric m6A quantification, we profiled parental, tamoxifen and exemestane resistant MCF7 derivatives. Tamoxifen-resistant cells exhibited ∼2,600 m6A sites with canonical DRACH motifs with widespread hyper- and hypomethylation across transcripts encoding MAPK regulators, receptor tyrosine kinases, and cell-cycle-associated kinases. Multi-omic integration including RNA-seq and quantitative proteomics indicate differentially methylated kinase mRNAs gained stability, enhanced translational efficiency and increased protein output, establishing an m6A-dependent mechanism of kinase reprogramming. Resistant cells also displayed selective upregulation of m6A-associated RNA-binding proteins, including YTHDF1 and IGF2BP2, consistent with a remodeled post-transcriptional landscape. Together, our findings uncover a previously underappreciated epitranscriptomic layer integrating quantitative m6A dynamics and RNA-binding protein shifts that drives kinase reprogramming and promotes ETR in breast cancer. Citation Format: Attila Szenasi, Enakshi Sivasudhan, Santiago Haase, Austin Whitman, Kate D. Meyer, Philip M. Spanheimer. m6A-mediated control of kinase reprogramming in endocrine therapy-resistant breast cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1794.
Szénási et al. (Fri,) studied this question.