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

Combination therapies and multi-targeted drugs have been proposed as strategies to prevent the emergence of resistant clones, potentially improving long-term treatment efficacy and clinical outcomes for cancer patients. NT157 is a synthetic tyrphostin that leads to sustained inhibition of IGF1R/IRS1-2, STAT3, and AXL-mediated signaling pathways. Given the critical role these pathways play in the development and progression of lung cancer, this disease serves as an ideal model for generating preclinical insights into the cellular and molecular mechanisms underlying NT157’s antineoplastic activity. In lung cancer cells, NT157 exposure reduced cell viability, clonogenicity, cell cycle progression, and migration in a dose-dependent manner, while also inducing apoptosis (p < 0.05). At the molecular level, NT157 decreased the expression of IRS1 and AXL and reduced phosphorylation of p38 MAPK, AKT, and 4EBP1. Additionally, NT157 lowered the expression of oncogenes BCL2, CCND1, MYB, and MYC, while upregulating genes associated with cellular stress and apoptosis, including JUN, BBC3, CDKN1A, CDKN1B, FOS, and EGR1 (p < 0.05), thereby promoting a tumor-suppressive cell signaling network in lung cancer. Notably, JNK was identified as a key kinase for NT157-induced phosphorylation of IRS1 and IRS2, revealing a novel pathway involved in the drug’s mechanism of action. NT157 also enhanced the effects of EGFR inhibitors in lung cancer cells. In conclusion, our preclinical findings position NT157 as a promising multitarget drug candidate that could expand the therapeutic options available for lung cancer treatment.