Abstract Endocrine therapy has substantially improved outcomes in hormone receptor-positive (HR+) breast cancer, yet resistance remains a major clinical challenge. Such resistance arises via two axes: spatially from tumor-intrinsic alterations or microenvironmental cues; temporally as de novo or acquired phenotypes. How these diverse drivers converge to reprogram cancer cell states remains poorly understood. Through single-cell transcriptomics of resistant HR+ breast cancers, we uncovered a recurrent luminal-to-basal transition with ER/PR downregulation - plasticity that emerged in primary tumors and amplified in metastases, particularly malignant pleural effusions (MPE). Using serial drug selection and MPE coculture, we recapitulated both therapy-induced and microenvironment-driven resistance, both of which converged on FGFR and JAK pathways activation—a phenotype reversible by genetic knockdown or pharmacological inhibition of these pathways. Mechanistically, FGFR and JAK activation regulated transcription factors to repress luminal genes (ESR1, PGR) and conferred resistance. Tinengotinib (TT-00420), a first-in-class dual FGFR and JAK small molecular inhibitor, restored luminal identity and resensitized resistant models to endocrine therapy in vitro and in vivo. Thus, lineage plasticity unified intrinsic/extrinsic inputs in endocrine resistance, supporting dual FGFR-JAK blockade as a translational strategy. Planned trials of tinengotinib combined with endocrine therapy in advanced HR+ breast cancer will assess its clinical potential, with results reported in due course. Citation Format: Yucheng Zeng, Ruixin Liu, Xiaoyan Qiang, Jean Fan, Caixia Sun, Hanlin Zeng, Peng Peng. Convergent FGFR-JAK signaling reprograms luminal identity and drives endocrine resistance in HR+ 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 1786.
Zeng et al. (Fri,) studied this question.