Poster Presentation 30th Lorne Cancer Conference 2018

Reactivation of RAS/ERK signalling facilitates PI3K/AKT/mTORC1-dependent cellular senescence evasion (#132)

Keefe T Chan 1 , Shaun Blake 1 , Haoran Zhu 1 2 , Jian Kang 1 , Piyush Madhamshettiwar 3 , Jeannine Diesch 4 , Katherine M Hannan 5 6 , Amee J George 5 7 , Ross D Hannan 1 2 5 6 7 8 , Kaylene J Simpson 2 3 , Rick B Pearson 1 2 6 8
  1. Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
  2. Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia
  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. Department of Biochemistry and Molecular Biology, University of Melbourne, Melbourne, VIC, Australia
  7. School of Biomedical Sciences, University of Queensland, Brisbane, QLD, Australia
  8. Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, Australia

One-third of all sporadic human cancers display aberrant activation of the PI3K/AKT/mTORC1 signalling network, which is essential for homeostatic processes involving cell growth, proliferation, and survival. Fine-tuned regulation of this rheostat is, therefore, an intrinsic safeguard against malignant progression. Despite substantial investigation into anti-proliferative therapies targeting the PI3K/AKT/mTORC1 pathway in cancer, a gap remains in our understanding of how persistent signalling promotes arrest in normal cells by oncogene-induced senescence (OIS) and whether this could be exploited to reverse the transformed phenotype. Here, we use transcriptome profiling and whole genome RNAi screening to uncover regulators of PI3K/AKT/mTORC1-dependent OIS. In particular, we identify that suppression of RAS/ERK signalling is required for OIS maintenance while its reactivation potentiates evasion and transformation. Toggling RAS/ERK activity in ovarian cancer cells displaying chronic PI3K/AKT/mTORC1 activation enables switching between cycling and a cytostatic state exhibiting multiple markers of cellular senescence. Together, our findings raise the possibility of combining inhibitors of RAS/ERK signalling with therapies such as checkpoint inhibitors or those that selectively kill senescent cells (senolytics) to combat PI3K/AKT/mTORC1-driven cancers.