Abstract 5529: Development and characterization of BRAF/MEK inhibitor resistant anaplastic thyroid carcinoma patient-derived xenograft and cell line models

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Abstract Introduction: Anaplastic Thyroid Carcinoma (ATC) is one of the deadliest malignancies with 5-month median overall survival (OS). Treatment of BRAFV600E-mutated (BRAFm) ATC with BRAF/MEK inhibitors (BRAF/MEKi) revolutionized disease management and improved median OS to 16 months for this subgroup. However, like other BRAFm cancers, tumors develop resistance within a few months, and patients are often inoperable, making tumor specimen retrieval difficult for studying resistance development. The utilization of patient-derived xenograft (PDX) models and cell lines (CDX) is therefore an integral part of disease mechanism understanding and therapeutics development. To date, there is no BRAF/MEKi resistant ATC model available in the scientific community. Aim: Report the development and characterization of a BRAF/MEKi resistant ATC cell-line and PDX models. Methods: Our group previously established and characterized BRAFm ATC PDX models. MDA-ATC1 is BRAFV600E, TP53, TERT, PI3K-mutated. These were implanted in 5-8-week-old nu/nu nude mice and treated with dabrafenib+trametinib (D/T) 15mg/kg+0.5mg/kg, at half or full dose, followed by dose doubling of D once resistance was observed. For CDX modelling, MDA-T220 (BRAFV600E, TP53, TERT, and PI3K mutated, from patient previously treated with D/T) was implanted into 6-12-week-old NSG mice and treated with two D+T concentrations (low: 15mg/kg + 0.25mg/kg and high: 30mg/kg + 0.5mg/kg) once tumors reached ∼200mm3. Successful establishment of resistant PDX & CDX models was determined when tumors continued to grow beyond 1000mm3 despite maximum dose escalation, and if growing following cryopreservation for the PDX models. Results/Discussion: At first passage, resistance to BRAF/MEKi was detected in MDA-ATC1 at week 12 for half and 18 for full dose. On second & third passage, tumors continued to show resistance, even following dose escalation. Resistance in the CDX was observed during the initial treatment period and tumor growth continued under consistent low and high D/T dosing concentrations. The first passage tumors grew rapidly under both dosing concentrations and were subsequently used in the second passage for dose escalation and resistance maintenance studies until tumors reached >1000mm3. At each passage and at study completion, tumors from PDX and CDX models were harvested and evaluated with short tandem repeats, immunohistochemistry for BRAF-status, and standard H&E staining. Conclusion: To our knowledge, these are the first BRAF/MEKi resistant ATC models described and characterized. We expect these models to play an integral role in drug development and evaluation for this difficult-to-treat population with no adequate therapeutic option to date. Citation Format: Ahmad Abubaker, Meredith Miller, Ying Henderson, Brooke Meyers, Ningping Feng, Stephen Wang, Jessica Molkentine, Andy Zuniga, Virginia Giuliani, Stephen Y. Lai, Christopher Terranova, Anastasios Maniakas. Development and characterization of BRAF/MEK inhibitor resistant anaplastic thyroid carcinoma patient-derived xenograft and cell line models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5529.

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