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NT157 exerts antineoplastic activity by targeting JNK and AXL signaling in lung cancer cells

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Lins de Miranda, Livia Bassani ; Lima, Keli ; Coelho-Silva, Juan Luiz ; Traina, Fabiola ; Kobayashi, Susumu S. ; Machado-Neto, Joao Agostinho
Número total de Autores: 6
Tipo de documento: Artigo Científico
Fonte: SCIENTIFIC REPORTS; v. 12, n. 1, p. 11-pg., 2022-10-12.

Combination therapies or multi-targeted drugs have been pointed out as an option to prevent the emergence of resistant clones, which could make long-term treatment more effective and translate into better clinical outcomes for cancer patients. The NT157 compound is a synthetic tyrphostin that leads to long-term inhibition of IGF1R/IRS1-2-, STAT3- and AXL-mediated signaling pathways. Given the importance of these signaling pathways for the development and progression of lung cancer, this disease becomes an interesting model for generating preclinical evidence on the cellular and molecular mechanisms underlying the antineoplastic activity of NT157. In lung cancer cells, exposure to NT157 decreased, in a dose-dependent manner, cell viability, clonogenicity, cell cycle progression and migration, and induced apoptosis (p < 0.05). In the molecular scenario, NT157 reduced expression of IRS1 and AXL and phosphorylation of p38 MAPK, AKT, and 4EBP1. Besides, NT157 decreased expression of oncogenes BCL2, CCND1, MYB, and MYC and increased genes related to cellular stress and apoptosis, JUN, BBC3, CDKN1A, CDKN1B, FOS, and EGR1 (p < 0.05), favoring a tumor-suppressive cell signaling network in the context of lung cancer. Of note, JNK was identified as a key kinase for NT157-induced IRS1 and IRS2 phosphorylation, revealing a novel axis involved in the mechanism of action of the drug. NT157 also presented potentiating effects on EGFR inhibitors in lung cancer cells. In conclusion, our preclinical findings highlight NT157 as a putative prototype of a multitarget drug that may contribute to the antineoplastic arsenal against lung cancer. (AU)

Processo FAPESP: 19/23864-7 - Análise compreensiva de dados genômicos para identificação e validação de novos alvos terapêuticos envolvidos na regulação de citoesqueleto celular em Leucemias agudas
Beneficiário:João Agostinho Machado Neto
Modalidade de apoio: Auxílio à Pesquisa - Regular
Processo FAPESP: 20/12748-3 - Investigação dos efeitos de NT157, fármaco com múltiplos alvos anticâncer, em modelos celulares de câncer de pulmão
Beneficiário:Lívia Bassani Lins de Miranda
Modalidade de apoio: Bolsas no Brasil - Iniciação Científica
Processo FAPESP: 21/11606-3 - Investigação dos efeitos antineoplásicos de novos inibidores de PIP4K2 e HDAC em neoplasias hematológicas
Beneficiário:João Agostinho Machado Neto
Modalidade de apoio: Auxílio à Pesquisa - Regular