ANTIPARASITIC DRUG IVERMECTIN EXHIBITS ANTITUMOR ACTIVITY IN PANCREATIC DUCTAL ADENOCARCINOMA MODELS

GONZÁLEZ MORÁN F; SOLERNÓ LM; LLAVONA C; FARINA HG; DUSETTI N; IOVANNA J; SEGATORI VI; GARONA J; ALONSO DF; GOTTARDO MF

Congreso; REUNION ANUAL DE SOCIEDADES DE BIOCIENCIA; 2023

Sociedad Argentina de Investigación Clínica

Pancreatic ductal adenocarcinoma (PDAC) is the fourth leadingcause of cancer-related deaths worldwide. In addition, its 5-yearsurvival rate is less than 5% due to late diagnosis and limited treat-ment options. Ivermectin (IVM) is a widely used antiparasitic drugthat has been repositioned as an antitumor agent given its capacityto reverse multidrug resistance, inhibit proliferation and decreasemitochondrial biogenesis. The aim of the present preclinical studywas to investigate the antitumor effects of IVM in PDAC. UsingTCGA GTEX databases and the UCSC Xena and GEPIA2 plat-forms (PAAD/n=179), we explored putative molecular targets asso-ciated with IVM mechanisms (i.e. CARL; PAK1; ERK1), confirmingtheir overexpression in cancer tissue, and its direct correlation withworse prognosis. Employing the Tumor Immune Estimation Re-source (TIMER2.0) platform we found a strong positive associationbetween the expression of several IVM targets and the infiltrationlevels of cancer-associated fibroblasts as well as myeloid-derivedsuppressor cells in PDAC clinical samples. In vitro, PANC-1 and PANC02 cell lines showed a high sensitivity to IVM, obtaining anIC50 of ≈10 μM on cell viability. Treatment with low concentrations ofIVM also inhibited colony-formation, clonogenic growth, tumor cellmetabolism and chemotaxis. In addition, IVM treatment reducedmitochondrial transmembrane potential, a well-known immunogeniccell death molecular marker (p