Analysis of pulsed cisplatin signalling dynamics identifies effectors of resistance in lung adenocarcinoma.
Authors
Hastings, Jordan FGonzalez Rajal, Alvaro
Latham, Sharissa L
Han, Jeremy Zr
McCloy, Rachael A
O'Donnell, Yolande Ei
Phimmachanh, Monica
Murphy, Alexander D
Nagrial, Adnan
Daneshvar, Dariush
Chin, Venessa
Watkins, D Neil
Burgess, Andrew
Croucher, David R
Issue Date
2020-06-09Keywords
P70S6Kcancer biology
chemoresistance
human
lung adenocarcinoma
p53
platinum chemotherapy
signalling dynamics
Metadata
Show full item recordJournal
eLifeDOI
10.7554/eLife.53367PubMed ID
32513387Abstract
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.Item Type
ArticleOther
Language
enEISSN
2050-084Xae974a485f413a2113503eed53cd6c53
10.7554/eLife.53367