Abstract 6179: Differential sensitivity of paired FUS-TFCP2+ RMS PDX models developed from tumor specimens obtained prior to and after ALK inhibitor therapy

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Abstract FUS-TFCP2-positive rhabdomyosarcoma (FUS-TFCP2+ RMS) is a rare subtype of spindle cell/sclerosing RMS with a craniofacial predilection. These tumors are highly aggressive, quick to metastasize and evade conventional chemotherapies. FUS-TFCP2 fusion results in a gain of function transcription factor that promotes proliferation and activates survival pathways while blocking myogenic differentiation and inhibiting DNA repair. Currently, there is no effective standard of care, surgery can be difficult due to location and patients typically succumb to the disease within 15 months of diagnosis. Overexpression of downstream target, Anaplastic Lymphoma Kinase (ALK), is characteristic of FUS-TFCP2+ RMS. However, while case reports of targeted treatment with ALK inhibitors (ALKi) have shown modest results, resistance always emerges. In collaboration with the Pediatric Cancer Precision Genomics Program at the Riley Hospital for Children, we developed a paired set of FUS-TFCP2+ RMS patient-derived xenografts (PDXs). ALKi-sensitive PDX174 was derived from a patient tumor sample obtained prior to an 11-month ALKi (lorlatinib) regimen. Subsequently, a second sample was acquired following disease progression from which ALKi-resistant PDX199 was established. RT-PCR validated the fusion site in both models. In vivo studies confirmed PDX174 sensitivity and PDX199 resistance to lorlatinib (0.1mg/kg and 1mg/kg). Concordant with FUS-TFCP2+ characterization, transcriptome analysis showed significantly increased expression of ALK in both PDX174 (14.9-fold) and PDX199 (11.1-fold). Western blot analysis revealed robust overexpression of ALK isoforms in PDX174, whereas ALK expression in the ALKi-resistant PDX199 was only barely detectable. Instead, PDX199 exhibited increased levels of TERT, CDK4/6, and BET proteins. To further compare the models, we utilized two complementary approaches to evaluate the activated kinome of ALKi-resistant PDX199 compared to ALKi-sensitive PDX174. Kinase activity profiling using PamGene peptide microarrays revealed a statistically significant increase in kinase activity of components involved in PI3K/AKT pathway and cell cycle CDKs (CDK1,2,4), with concomitant suppression of kinase activity of JNK/p38 MAPKs, indicating a shift toward PI3K/mTOR-driven pro-survival signaling and potential vulnerability to PI3K/AKT and CDK inhibition. Global kinome analysis using multiplexed inhibitor beads also showed an increase in CDK4/6 activation in ALKi-resistant PDX199 versus ALKi-sensitive PDX174. Pre-clinical models such as these provide a platform to connect molecular signatures with targeted therapy, increase our mechanistic understanding of tumor adaptive responses and design therapies that will mitigate the emergence of therapeutic resistance. Citation Format: Erika Dobrota, M. Reza Saadatzadeh, Barbara Bailey, Keiko Kreklau, Gabe Mervis, Kathy Coy, Felicia Kennedy, Melissa Trowbridge, Anthony Sinn, Christopher Davis, Steven Angus, Michael Ferguson, Pankita Pandya, Karen Pollok. Differential sensitivity of paired FUS-TFCP2+ RMS PDX models developed from tumor specimens obtained prior to and after ALK inhibitor therapy [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 6179.

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