Dados do Resumo

Título

The decrease of PD-L2 with BET and EGFR inhibitors combination in non–small-cell lung cancer

Introdução

Non-small cell lung cancer (NSCLC) remains one of the leading causes of cancer-related mortality. Mutations in EGFR are frequent in NSCLC and Osimertinib (EGFR inhibitor - EGFRi), has demonstrated efficacy in managing NSCLC. However, despite initial responses, resistance to Osimertinib can develop. New targets such as BET family proteins have been explored, and the use of BET inhibitors (BETi) have shown preclinical antitumor response.

Objetivo

Our aim is to evaluate the effects of BET and EGFR inhibitors in NSCLC cell line.

Métodos

We used H1975 NSCLC cell line in all the experiments. Cell viability was analyzed by colorimetric colony staining. Annexin V was used to detect apoptotic cells and propidium iodide (PI) was applied to cell cycle analysis. Gene expression was analyzed by RT-qPCR for the following genes (MYC, PD-L1, PD-L2). Flow cytometer was used to detect the surface proteins PD-L1 and PD-L2.

Resultados

We demonstrated decreased cell proliferation in EGFRi treatment alone or in combination with BETi when compared to the control (vehicle - DMSO). The same was observed in apoptosis assay, with increased cell death in EGFRi and in the combination with BETi when compared to control. EGFRi alone or in combination with BETi was also able to cause cell cycle arrest in G1 phase, which was associated with decreased MYC gene expression in these groups. When we focused on immune checkpoint co-receptors expression, we also noticed a decrease of PD-L1 in EGFRi treatment (alone or combined) compared to control. Curiously, the PD-L2 was decreased in EGFRi and BETi isolated treatments and the combined treatment could diminish even more the expression of this gene and the cell surface presence of PD-L2.

Conclusões

We conclude that BETi contributed to the anti-tumoral effect of EGFRi treated cells and diminished PD-L2 expression. These data indicate that further studies could amplify the proposition of EGFRi and BETi combination as a therapeutic approach to NSCLC and a potential treatment to improve tumor immune cells recognition.

Palavras Chave

Non-small cell lung cancer; Epigenetic inhibitors; Immune-checkpoint