TY - JOUR T1 - HUMAN PANCREATIC CANCER CELLS UNDERGO PROFOUND METABOLIC REPROGRAMMING TOWARDS CELLULAR STEMNESS AS ADAPTATION TO INHIBITION OF THE AKT PATHWAY JF - bioRxiv DO - 10.1101/2020.04.01.020446 SP - 2020.04.01.020446 AU - Hugo Arasanz AU - Carlos Hernández AU - Ana Bocanegra AU - Luisa Chocarro AU - Miren Zuazo AU - Maria Gato AU - Karina Ausin AU - Enrique Santamaría AU - Joaquín Fernández-Irigoyen AU - Gonzalo Fernandez AU - Eva Monasterio AU - Carlos Rodríguez AU - Idoia Blanco AU - Ruth Vera AU - David Escors AU - Grazyna Kochan Y1 - 2020/01/01 UR - http://biorxiv.org/content/early/2020/04/02/2020.04.01.020446.abstract N2 - Cancer cells acquire resistance to cytotoxic therapies targeting major survival pathways by adapting their metabolism. The AKT pathway is a major regulator of human pancreatic adenocarcinoma progression. The mechanisms of adaptation to long-term silencing of AKT isoforms of pancreatic cancer cells were studied. Following silencing, cancer cells remained quiescent for long periods of time, after which they recovered proliferative capacities. Adaptation caused profound proteomic changes largely affecting mitochondrial biogenesis, energy metabolism, and acquisition of a number of distinct cancer stem cell (CSC) characteristics depending on the AKT isoform that was silenced. The adaptation to AKT1 silencing drove most de-differentiation and acquisition of stemness through C-MYC down-modulation and NANOG up-regulation, which were required for survival of adapted CSCs. The changes associated to adaptation sensitized cancer cells to inhibitors targeting regulators of oxidative respiration and mitochondrial biogenesis. In vivo pharmacological co-inhibition of AKT and mitochondrial metabolism effectively controlled pancreatic adenocarcinoma growth in pre-clinical models. ER -