Evaluation of proteomic changes in the spliceosome in resistant chronic myeloid leukemia cells with the T315I mutation.

• Grant number: 24/11153-7
• Support Opportunities: Scholarships in Brazil - Master
• Start date: April 01, 2025
• End date: February 28, 2026
• Field of knowledge: Biological Sciences - Biochemistry
• Principal Investigator: Vitor Marcel Faça
• Grantee: Adrieli Silva de Carlis
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

Chronic myeloid leukemia (CML) is characterized by the presence of the BCR-ABL1 oncoprotein, with constitutive activation of its tyrosine kinase activity and the neoplastic transformation of hematopoietic stem cells. The development of tyrosine kinase inhibitors (TKIs) specific for BCR-ABL1, such as imatinib mesylate, represented a breakthrough in the treatment of CML. However, therapeutic challenges remain, as observed in the case of the T315I mutation, which confers resistance to all available TKIs. The identification of the association between IRS1 protein and BCR-ABL1, and the demonstration of the antineoplastic effects of the pharmacological inhibitor NT157 of IGF1R-IRS1/2 in cell models, independent of the T315I mutation, have opened new perspectives for reducing the impact of resistance in patients. Consequently, there is a need for complementary therapies targeting molecular coadjuvants of BCR-ABL1's transforming action. There is evidence that CML cells are dependent on the spliceosome, and pharmacological inhibition of this machinery can selectively affect the survival of tumor cells. Targeting spliceosome inhibitors is a new therapeutic strategy, showing promising results in solid tumors and hematopoietic malignancies. Several drugs have the potential to study the numerous cellular pathways affected by splicing and the spliceosome components themselves, such as Erythromycin and Clotrimazole. However, there are no clinical studies using these drugs for therapeutic purposes in CML. Therefore, the oral drug H3B-8800 will also be used in this project, as it stands out in clinical studies by demonstrating to be an inhibitor of molecules from the spliceosome's SF3b complex. In summary, we will explore alterations in the spliceosome in the model of Ba/F3 WT leukemic cells and imatinib-resistant Ba/F3 T315I cells in CML. With this, we hope to expand a new frontier of cancer research focused on the splicing interrelations involving its manifestations in proteomics, which has significant potential to elucidate new tumor targets involved in cancer, with possible impacts on the application of new drugs for the treatment of imatinib-resistant CML.