Pancreatic cancer is recognised as a neoplasm with high global lethality, mainly due to late diagnosis resulting from the rarity of symptoms at early stages and low responsiveness to currently available therapies. Certain pathways involved in growth, proliferation and survival processes of tumour cells have been well established in the literature, such as the IGF1R, STAT3 and PI3K/AKT pathways. Among these, the IGF1R pathway stands out as the target of the inhibitor NT157 and is responsible for the activation of IRS1/2 and PI3K/AKT. In addition to IGF1R, the compound NT157 also interferes with the activation of the transcription factor STAT3 through the modulation of phosphatase proteins, reinforcing its antineoplastic potential.

To analyze the effects of the compound NT157 in the pancreatic cancer cell lines MIA PaCa-2, PANC-1 and AsPC-1.

The MIA PaCa-2, AsPC-1 and PANC-1 cell lines were treated with vehicle or NT157 and evaluated for cell viability using the MTT assay and clonogenic capacity using the colony formation assay. The expression of proteins related to proliferation, cell cycle regulation, apoptosis, DNA damage and signaling pathways was analyzed by Western blot following treatment. Cell cycle distribution was examined by propidium iodide staining. Data were analyzed using appropriate statistical methods.

NT157 reduced cell viability and clonogenic capacity in all pancreatic cancer cell lines analyzed. The MIA PaCa-2 cell line showed greater sensitivity to the drug compared with the AsPC-1 and PANC-1 cell lines. At the molecular level, NT157 treatment modulated proteins associated with proliferation, cell cycle control, apoptosis and DNA damage. In MIA PaCa-2 and AsPC-1 cells, increase in inhibitory phosphorylation of IRS1/2 and activation of ERK and JNK were observed, whereas in PANC-1 cells there was an increase in total IRS1/2 forms. All cell lines exhibited reduced AXL expression and decreased STAT3 signaling. Apoptosis induction was evidenced by PARP1 cleavage in all cell lines, while increased H2AX levels were observed in MIA PaCa-2 and PANC-1. Cell cycle analysis revealed G2/M accumulation in MIA PaCa-2 and PANC-1 at higher doses. A dose-dependent increase in the sub-G1 fraction was reported in all cell lines.

The compound NT157 negatively interferes with the viability and proliferation of pancreatic cancer cells. Sensitivity to the drug was associated with differences in the activation of the IGF1R/IRS and AXL signaling pathways. Furthermore, NT157 promoted apoptosis, DNA damage and cell cycle arrest, reinforcing its potential as a therapeutic candidate for pancreatic cancer.