FGFR-JAK信号的汇聚重编程管腔身份并驱动HR⁺乳腺癌的内分泌治疗耐药

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.