FGFR2 (Fibroblast growth factor receptor 2)

We developed CYB-5067 by equipping the pan-FGFR inhibitor Infigratinib with a minimal dibromoacetamide covalent warhead...Our work identifies RNF213 as an exploitable ligase for TPD and establishes covalent molecular glues as a modular platform. This strategy expands the scope of degrader design beyond conventional E3 ligases, offering an avenue for developing potent and selective therapeutics.

The findings support continued investigation of FGFR-targeted strategies in FGFR2-amplified GC/GEJ adenocarcinoma, while underscoring the need for larger studies, refined biomarker selection, and deeper characterization of resistance mechanisms.

This case demonstrates the significant therapeutic potential of pemigatinib in a patient with metastatic cholangiocarcinoma with FGFR2 fusion, where complete disease remission was achieved after previous progression on standard treatment.

Exploratory grouping by the model-derived RiskScore revealed differences in pathway and immune infiltration patterns, suggesting an association between the signature and intratumoral molecular heterogeneity. These exploratory findings primarily serve to characterize the biological features related to the model and provide supplementary clues for understanding molecular alterations in prostate cancer; they should be interpreted with caution.

Clinical activity of FGFRi was heterogenous across FGFR alteration and tumor types. FGFR fusions and mutations were associated with greater benefit, whereas amplifications were not. Further investigation of resistance mechanisms and development of next-generation FGFRi are needed.

We demonstrated the real-world genomic characteristics of BTC patients, which may have promising implications for the development and application of precision medicine in the future. Well-designed prospective studies are mandatory to validate the predictive role of significant genomic alterations observed in our study.

Personalized treatment recommendations were made for 13 patients, and 11 received matched therapies: dabrafenib ± trametinib (n = 9), futibatinib (n = 1), or binimetinib (n = 1). These findings demonstrate frequent actionable alterations in ameloblastoma and clinically meaningful responses of targeted therapies. Incorporating precision oncology into standard care may facilitate personalized, less morbid surgery and improved outcomes in these rare tumors.

The contemporary therapeutic landscape integrates targeted agents with immune checkpoint inhibitors; yet, optimal treatment sequencing and biomarker-driven patient selection require further refinement. This review synthesizes current evidence-based approaches and emerging therapeutic paradigms in hepatobiliary oncology, examining how molecular characterization can bridge the precision medicine gap between BTC and HCC to improve patient outcomes.

CNS involvement in ACC was associated with poor outcomes despite multimodal therapy. NOTCH1 alterations and leptomeningeal disease were frequent in this cohort, but these findings should be interpreted as hypothesis-generating given the small sample size and absence of a matched non-CNS comparator cohort.

In this study, by incorporating diverse molecular glue handles and amino acid-based degrons into the solvent-exposed exit vectors of infigratinib, we synthesized a library of 30 candidate MGDs...Mechanistic investigations revealed that the covalent engagement of the gluing handle is a critical determinant for successful proteasomal degradation of FGFR2. This work provides a framework for the rational transformation of kinase inhibitors into covalent molecular glue degraders, underscoring the potential of FGFR degradation as a next-generation precision medicine strategy for FGFR2-driven malignancies.

Functionally, KNT-0919 selectively suppressed the proliferation of FGFR2-dependent cancer cell lines, dose-dependently inhibited FGFR2 downstream signaling, and induced apoptosis in an FGFR2-dependent manner. Moreover, KNT-0919 demonstrated favorable oral bioavailability (56%) in rats and achieved significant tumor growth inhibition in an SNU-16 gastric cancer xenograft model.

Pemigatinib (approved in 2021) demonstrated a response rate of 35.5%, futibatinib (approved in 2023) showed a response rate of 42%, and tasurgratinib (approved in 2024) achieved a response rate of 30.2%. Polyclonal on-target resistance to pan-FGFR inhibitors and increasing of FGFR2 kinase domain resistance mutations based on treatment history has been reported. Novel therapeutics, such as highly selective FGFR2 inhibitors and next-generation inhibitors, are developed and are expected to improve prognosis for patients with FGFR2 fusion-positive solid tumors.