Abstract
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 and a key pharmacological target. The mechanisms of adaptation to long-term silencing of AKT isoforms of human and mouse pancreatic adenocarcinoma 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 upregulation, 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.
Highlights
Phosphatidyl inositol 3-phosphotase kinase/AKT/molecular target of rapamycin (PI3K/AKT/mTOR) signaling axis constitutes a central pathway involved in progression of pancreatic adenocarcinoma
The PI3K-AKT signaling axis is one of the major pathways associated to pancreatic cancer cell progression
We decided to investigate the mechanisms by which cancer cells become resistant to its prolonged inhibition by interfering with the expression of each of the AKT isoforms, hoping that this information may identify the most critical isoform for adaptation
Summary
MTOR) signaling axis constitutes a central pathway involved in progression of pancreatic adenocarcinoma. AKT-mTOR-targeted therapies are clinically ineffective as tumor cells adapt to overcome inhibition of this key signaling axis [1,2,3]. Escape of tumor cells from cytotoxic therapies has been associated to selection of variants with resistance mutations present within a heterogeneous population of tumor cells. Recent evidence indicates that treatment-resistant tumors arise from a population of cancer stem cells (CSC) derived from within a collection of metabolically plastic cancer cells in the tumor [4]. Whether treatment-resistant cells come from a pre-existing small population of CSCs or they are selected by metabolic adaptation through a process of de-differentiation is still a matter of debate
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