ECEESPE2025 Poster Presentations Pituitary, Neuroendocrinology and Puberty (162 abstracts)
Repurposing dasatinib, an FDA-approved tyrosine kinase inhibitor, for the treatment of aggressive pituitary tumors
Sophia Mercado-Medrez 1,2 , Daniel Marrero-Rodríguez 1 , Everardo Curiel-Quesada 2 , Gloria León-Ávila 2 , Ma Isabel Salazar-Sánchez 2 , Eduardo Vadillo 3 , Antonieta Chávez-González 3 , Ana Ortiz-Reyes 3 , Sergio García-Sánchez 3 , Víctor Adrián Cortés-Morales 4 , Blas Lopez-Felix 5 , Leilani Reyna-Coahutle 1,2 , Mayte Padilla-Cristerna 1,2 , Florencia Martinez-Mendoza 1 , Keiko Taniguchi-Ponciano 1 & Moisés Mercado 1
1Unidad de Investigación Médica en Enfermedades Endocrinas, Hospital de Especialidades, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Mexico, Mexico; 2Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Mexico, Mexico; 3Unidad de Investigación Médica en Enfermedades Oncológicas, Instituto Mexicano del Seguro Social, Mexico, Mexico; 4Unidad de Investigación Médica en Inmunoquímica, Hospital de Especialidades, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Mexico, Mexico; 5Servicio de Neurocirugía, Hospital de Especialidades, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Mexico, Mexico
JOINT89
Introduction: Pituitary tumors (PT) occasionally exhibit an aggressive behavior, being invasive and resistant to treatment, growing rapidly and presenting multiple recurrences. We conducted a transcriptomic analysis of 22 tumors from 11 patients, including both primary and recurrent tumors from the same individuals. We identified several differentially expressed genes that are involved in lipid-related pathways, such as the up-regulation of diacylglycerol kinase gamma (DGKG), also confirmed by immunofluorescence and rt-PCR in another cohort of PT. Moreover, with molecular docking and drug repurposing tools, we observed that dasatinib, a tyrosine kinase inhibitor (TKI) already approved by the FDA for chronic myelogenous leukemia, has DGKG as a potential therapeutic target. Additionally, a novel small molecule targeting kinases (KPG-04) was designed, and its ability to induce apoptosis and decrease cell proliferation was tested.
Methods: GH3 cells and primary PT cultures were exposed to dasatinib and KPG-04 at increasing concentrations and cell viability and apoptosis were assessed by means of flow cytometry. PT samples were obtained surgically and immediately disassociated enzymatically.
Results: Exposure of GH3 cells to dasatinib decreased cellular proliferation in a dose-dependent manner: 28% at 1 μM (P = 0.0048), 50% at 2.5 μM (P = 0.003) and 98% at 5 μM (P = 0.0395). Dasatinib also resulted in apoptosis induction at concentrations as low as 1 μM and increasing progressively with 2.5 μM and 5 μM (P = 0.0001). Significantly higher concentrations of KPG-04 were required to induce cell proliferation arrest (57.23% at 50 μM, P = 0.0039; 68.95% at 75 μM; and 74.58% at 100 μM) and had no effect on apoptosis. Similarly, preliminary results showed that exposure of PT primary cultures to dasatinib resulted in a reduction in cellular proliferation and apoptosis induction.
Conclusion: Dasatinib, but not KPG-04, induces apoptosis and decreases cell viability in a dose-dependent manner starting at very low, probably non-toxic concentrations in both, a murine mamosomatotrope cell line and in PT primary cultures. This opens a new perspective in the treatment of aggressive PT resistant to conventional multimodal therapy, but prospective clinical studies are needed to ascertain the efficacy and safety of this TKI. We are currently designing new small molecules capable of targeting kinases such as DGKG.
Volume 110
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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