2026-07-09 | BRAF V600E in Anaplastic Thyroid Carcinoma: Reproducibility Archive
BRAF V600E regional disparities in Anaplastic Thyroid Carcinoma: Reproducibility Archive for "Is BRAF V600E Truly That Common in Anaplastic Thyroid Carcinoma? A Systematic Review and Meta-Analysis
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2026-07-07 | [Gilteritinib enhances the inhibitory effect of dabrafenib on anaplastic thyroid carcinoma cells by suppressing the AXL signaling pathway].
To investigate the inhibitory effect of combined gilteritinib and dabrafenib treatment on anaplastic thyroid cancer (ATC) cells and its underlying mechanisms. The BRAF V600E-mutant ATC cell line 8505C and the BRAF wild-type ATC cell line KHM-5M were treated with various concentrations of dabrafenib (0, 40, 80, 120, 160, 320 nmol/mL) and gilteritinib (0, 0.1, 0.2, 0.4, 0.6, 1.0, 2.0 μmol/mL), alone or in combination. Cell proliferation and viability were assessed using the CCK-8 assay, and the IC₅₀ was calculated. The inhibitory effect on cell migration was evaluated using the Transwell assay. To examine the impact of treatment sequence on the combined efficacy, ATC cells were pretreated with either dabrafenib or gilteritinib for 1, 4, or 6 h, followed by the addition of the other drug and further incubation for a total of 24 h, after which cell viability was measured. Western blotting was performed to detect the expression of proteins related to apoptosis, proliferation, AXL, and the RAS/RAF/MEK/ERK pathway. Furthermore, AXL siRNA knockdown experiments were conducted to validate the molecular mechanism by which AXL mediates the gilteritinib-enhanced sensitivity of ATC cells to dabrafenib. Both gilteritinib and dabrafenib inhibited ATC cell proliferation in a concentration-dependent manner. Gilteritinib significantly enhanced the inhibitory effect of dabrafenib on ATC cell viability, and the combination also showed significantly greater inhibition of cell migration than either monotherapy. Mechanistically, in both ATC cell lines, compared with dabrafenib alone, the combination with gilteritinib consistently further downregulated the expression of AXL/p-AXL, RAS, and RAF, and reduced total ERK/MEK protein levels. Simultaneously, the combination reversed the aberrant activation of p-MEK/p-ERK induced by dabrafenib monotherapy, promoted the expression of apoptosis-related proteins, and decreased the expression of proliferation-related proteins. Moreover, upon silencing of AXL, the IC₅₀ value of dabrafenib in the AXL-knockdown group was significantly reduced. Gilteritinib enhances the antitumor efficacy of dabrafenib against ATC cells by inhibiting the AXL signaling pathway and delaying MAPK pathway reactivation.
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2026-07-03 | ANXA2+ Small Extracellular Vesicles Drive Chemoresistance in Anaplastic Thyroid Cancer by Promoting XRCC5 Lactylation and Enhancing Non-Homologous End-Joining Repair.
Anaplastic thyroid carcinoma (ATC) is an exceptionally aggressive malignancy with dismal survival, largely due to intrinsic cisplatin resistance. This study identifies a novel mechanism by which small extracellular vesicles (sEVs) promote chemoresistance by enhancing DNA repair via protein lactylation. ATC cells secrete sEVs enriched with Annexin A2 (ANXA2). Upon delivery to recipient ATC cells, ANXA2 stabilizes the interaction between SRC kinase and lactate dehydrogenase A (LDHA), leading to increased LDHA phosphorylation (Y10), enzyme activity, and lactate production. The resulting lactate surge serves as a substrate for lysine lactylation. Ku80 (XRCC5) is identified as a key lactylation target at K265, catalyzed by the acyltransferase KAT5. This lactylation modification strengthens the interaction between Ku80 and its partner Ku70 (XRCC6), stabilizing the initial DNA-end binding complex in the non-homologous end-joining (NHEJ) repair pathway. Consequently, NHEJ efficiency is significantly enhanced, enabling ATC cells to rapidly repair cisplatin-induced DNA double-strand breaks and survive treatment. Genetic disruption of the XRCC5-K265 lactylation site or pharmacological inhibition of LDHA sensitizes ATC xenograft tumors to cisplatin, while in vitro, inhibition of the SRC/LDHA axis produces a similar chemosensitizing effect. This work unveils the ANXA2+ sEV/SRC/LDHA/lactate/XRCC5-lactylation axis as a critical driver of NHEJ-mediated chemoresistance in ATC, offering new potential therapeutic targets.
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