Analysis of pulsed cisplatin signalling dynamics identifies effectors of resistance in lung adenocarcinoma
Jordan F Hastings,
Alvaro Gonzalez Rajal,
Sharissa L Latham,
Jeremy ZR Han,
Rachael A McCloy,
Yolande EI O'Donnell,
Monica Phimmachanh,
Alexander D Murphy,
Adnan Nagrial,
Dariush Daneshvar,
Venessa Chin,
D Neil Watkins,
Andrew Burgess,
David R Croucher
Affiliations
Jordan F Hastings
The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, Australia
Alvaro Gonzalez Rajal
The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, Australia
Sharissa L Latham
The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, Australia; St Vincent's Hospital Clinical School, University of New South Wales, Sydney, Australia
Jeremy ZR Han
The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, Australia
Rachael A McCloy
The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, Australia
Yolande EI O'Donnell
The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, Australia
Monica Phimmachanh
The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, Australia
Alexander D Murphy
Crown Princess Mary Cancer Centre, Westmead and Blacktown Hospitals, Sydney, Australia
Adnan Nagrial
Crown Princess Mary Cancer Centre, Westmead and Blacktown Hospitals, Sydney, Australia
Dariush Daneshvar
Crown Princess Mary Cancer Centre, Westmead and Blacktown Hospitals, Sydney, Australia
Venessa Chin
The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, Australia; St Vincent's Hospital Clinical School, University of New South Wales, Sydney, Australia; St Vincent’s Hospital Sydney, Darlinghurst, Australia
D Neil Watkins
Hudson Institute of Medical Research, Victoria, Australia; Department of Molecular and Translational Medicine, School of Medicine, Nursing and Health Sciences, Monash University, Victoria, Australia; Research Institute in Oncology and Hematology, Cancer Care Manitoba, Winnipeg, Canada; Department of Internal Medicine, Rady Faculty of Health Science, University of Manitoba, Winnipeg, Canada
The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, Australia; St Vincent's Hospital Clinical School, University of New South Wales, Sydney, Australia; School of Medicine, University College Dublin, Belfield, Dublin, Ireland
The identification of clinically viable strategies for overcoming resistance to platinum chemotherapy in lung adenocarcinoma has previously been hampered by inappropriately tailored in vitro assays of drug response. Therefore, using a pulse model that closely mimics the in vivo pharmacokinetics of platinum therapy, we profiled cisplatin-induced signalling, DNA-damage and apoptotic responses across a panel of human lung adenocarcinoma cell lines. By coupling this data to real-time, single-cell imaging of cell cycle and apoptosis we provide a fine-grained stratification of response, where a P70S6K-mediated signalling axis promotes resistance on a TP53 wildtype or null background, but not a mutant TP53 background. This finding highlights the value of in vitro models that match the physiological pharmacokinetics of drug exposure. Furthermore, it also demonstrates the importance of a mechanistic understanding of the interplay between somatic mutations and the signalling networks that govern drug response for the implementation of any consistently effective, patient-specific therapy.
