Proteomic Profiling of Medullary Thyroid Cancer Identifies CAPN1 as a Key Regulator of NF1 and RET Fueled Growth

• DOI: 10.1089/thy.2024.0102
• Publication Date: 2025-01-27T14:15:01Z
• Authors: Eshan Khan; Hannah Hylton; Neel Rajan; Stephanie J. Bouley; Jalal K. Siddiqui; Swetha Rajasekaran; Ganesh R. Koshre; Hayden Storts; Anisley Valenciaga; Misbah Khan; Sandya Liyanarachchi; Francisco Fernandez; Xuguang Zheng; John Phay; Priya H. Dedhia; Jing Wang; James A. Walker; Matthew D. Ringel; Wayne O. Miles
• Keywords: Medullary Thyroid Cancer; Proto-Oncogene Proteins c-ret

Background: Medullary thyroid cancer (MTC) is a frequently metastatic tumor of the that develops from malignant transformation C-cells. These tumors most commonly have activating mutations within RET or RAS proto-oncogenes. Germline result in C-cell hyperplasia, and cause MTC pre-disposition disorder, multiple endocrine neoplasia, type 2A (MEN2A). Single-agent therapies for MTC, including vandetanib (VAN) cabozantinib all MTCs selpercatinib (SEL) RET-mutated lead to partial responses but are not curative. Methods: To identify new therapeutic targets we conducted proteomic profiling normal C-cells, cells, pre-malignant MEN2A patient samples, tumors. Results: From this analysis, identified CAPN1, member CALPAIN (CAPN) family endopeptidases, as widely upregulated samples. We found short hairpin RNA-mediated depletion CAPN1 inhibitors significantly reduced cell growth, colony formation, xenograft growth vivo. In addition, show synergize with VAN SEL vitro, maximizing apoptosis. Mechanistic experiments implicate inhibiting neurofibromin, encoded by NF1, stabilize NF1 protein levels diminish downstream RAS/RET activation AKT ERK. Conclusions: Our data suggest increased support RAS-fueled reducing levels. find combinatorial between maximal efficacy cells.