Poster Presentation 29th Lorne Cancer Conference 2017

A genome-wide RNAi screen identifies novel regulators of AKT-induced senescence (#134)

Keefe T Chan 1 , Shaun Blake 1 , Lassi Paavolainen 2 , Piyush Madhamshettiwar 3 , Jeannine Diesch 4 , Katherine M Hannan 5 , Amee J George 5 , Ross D Hannan 5 , Kaylene J Simpson 3 , Peter Horvath 6 , Rick B Pearson 1
  1. Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
  2. Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland
  3. Victorian Centre For Functional Genomics, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
  4. Josep Carreras Leukaemia Research Institute, Badalona, Barcelona, Spain
  5. Department of Cancer Biology and Therapeutics, John Curtin School of Medical Research, Australian National University, Canberra, ACT, Australia
  6. Synthetic and Systems Biology Unit, Hungarian Academy of Sciences, Szeged, Hungary

Dysregulation of the PI3K/AKT/mTORC1 signalling pathway occurs in up to one-third of all sporadic human cancers. Paradoxically, oncogenic activation of this network in non-transformed cells promotes senescence, which poses a significant barrier to malignant progression. Understanding the basis of oncogene-induced senescence will provide insight into cancer development and potentially identify novel therapeutic targets. Our previous work showed that hyperactivation of AKT results in senescence via a p53 and mTORC1-dependent mechanism (Astle et al, Oncogene 2011). To determine the genetic changes required to overcome AKT-induced senescence, we performed a genome-wide RNAi gain-of-function screen using multi-parametric readouts including cell number, proliferation, and senescence-associated beta-galactosidase (SA-βGal) staining. In addition, we have utilised machine learning and automated image analysis methods to classify distinct phenotypes of cells with SA-βGal staining. Using various genetic approaches, we are investigating the role of candidate tumour suppressor gene targets and how they can be exploited in cancer.