Effect of inhibition of NOTCH signaling in non-small-cell lung cancer

MARCELO GABRIEL STINSON; MARÍA JIMENA MOSNA; ABEL CARCAGNO

Mar del Plata

Congreso; 24. LXVII Reunión Anual de la Sociedad Argentina de Investigación Clínica; 2023

SAIC

Lung cancer is the second most frequent cancer worldwide, and the third one in Argentina. It is also the first cause of cancer-related deaths both globally and in Argentina. Non-small-cell lung cancer (NSCLC) represents approximately 85% of all lung cancer cases. 55% of NSCLC patients receive a diagnosis at advanced stages of the disease, with presence of distant metastatic foci, and have a 5-year relative survival rate of only 9%. There is accumulating evidence of the relevance of developmental pathways in carcinogenic processes. In particular, Notch signaling is a type of intercellular communication pathway with several roles in developmental processes. During development of the lung, Notch signaling plays crucial roles in processes such as proximo‐distal patterning, cell fate choice, cell proliferation, and apoptosis. The aim of this work was to evaluate the role of Notch signaling in the tumorigenicity of NSCLC cells. We used DAPT, a pharmacological inhibitor of the 𝛾-secretase, to downregulate the activity of the Notch pathway in A549 human adenocarcinoma cells as a model for NSCLC. A549 cells were treated for 7 to 9 days with 40 µM DAPT. Treated cells do not differ in viability from control cells (Trypan Blue exclusion). DAPT-treated cells show reduced adhesion time to the culture plate and decreased proliferative and clonogenic (low-density culture) capacities. Migration of treated cells is also impaired (wound healing). Furthermore, we also evaluated the effects of treatment with DAPT on spheroids of A549 cells. Treated spheroids are significant bigger, and seem to be less densely packed than control spheroids. Treated spheroids were also grafted onto the chorioallantoic membrane of chick embryos, where their original differences in dimensions were lost. In conclusion, this study suggests that Notch signaling plays a role in the tumorigenicity of NSCLC cells indicating its potential as a target for lung cancer treatment.