Hyperactivation of the PI3K/AKT/mTORC1 signalling pathway is a hallmark of many sporadic human cancers. However, we and others have demonstrated that chronic activation of this pathway in normal cells induces senescence, which effectively acts as a “brake” on the progression to malignancy. We hypothesise that specific genetic changes overcome this brake and permit the increased cell proliferation and transformation required for cancer development. Understanding the basis of oncogene-induced senescence in normal cells and how this is subverted in cancer cells will provide insight into the mechanism of cancer development and how it can be targeted.
Our previous work showed that AKT-induced senescence in normal human cells occurs via a p53 and mTORC1-dependent mechanism (Astle et al, Oncogene 2011). To further understand the critical mechanisms underlying AKT-induced senescence, we performed transcriptome profiling by RNA sequencing. Gene ontology analysis of differentially regulated genes between senescent and normal fibroblasts demonstrated significant upregulation of NF-kb target genes associated with a senescence-associated secretory phenotype (SASP), which is consistent with recent studies of mTORC1 signalling in SASP regulation (Laberge et al, Nat Cell Biol 2015; Herranz et al., Nat Cell Biol 2015). To determine the genetic changes required to overcome AKT-induced senescence, we have completed a genome-wide RNAi gain-of-function screen using multi-parametric readouts including cell number, proliferation, and senescence-associated beta-galactosidase staining. We identified 98 candidate gene targets, several of which are known and potential tumour suppressors. We are investigating how AKT governs these pathways and how they can be exploited in cancer.