Oral Presentation 2015 Annual Meeting of the Australasian Society for Dermatology Research

Elevated levels of PLK1 bypass the ATM-dependent G2 phase checkpoint arrest in melanoma cell lines (#8)

Loredana Spoerri 1 , Kelly Brooks 1 , KeeMing Chia 1 , Gavri Grossman 1 , Mareike Dahmer-Heath 1 , Dubravka Skalamera 1 , Bryan Burmeister 2 , Brian Gabrielli 1
  1. University Of Queensland Diamantina Institute, Woolloongabba, QLD, Australia
  2. Department of Radiation Oncology, Princess Alexandra Hospital, Woolloongabba, Queensland, Australia

Targeted therapy has recently proven to be a valuable tool in the treatment of advanced melanoma, however the rapid development of drug resistance underlines the need of novel therapeutic targets. Defective cell cycle checkpoints represent a fertile and relatively untapped ground for the identification of new, selective targets in melanoma and more generally, in cancer. In this study we have investigated the molecular mechanisms of a cell cycle checkpoint defect that we have previously found to affect an important proportion of melanoma cell lines. We have identified this checkpoint defect to be in the ATM-dependent signalling pathway and demonstrated that the main signalling initiator, the ATM kinase, is unexpectedly properly functional. We have shown that the bypass of checkpoint arrest is due to deregulation of another main component of the ATM-dependent signalling pathway, the PLK1 kinase. PLK1 activity was elevated in cells with the checkpoint defect, with inhibition of PLK1 being sufficient to recover the ATM-dependent checkpoint arrest. The elucidation of this novel cell cycle checkpoint defect mechanism, not only contributes to the understanding of the molecular mechanisms underlying cell cycle checkpoint defects in melanoma, but may also provide potential targets for the selective treatment of an important proportion of melanomas.