RT Journal Article
SR Electronic
T1 Dynamic analysis of pulsed cisplatin identifies effectors of resistance in lung adenocarcinoma
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 775924
DO 10.1101/775924
A1 Jordan F. Hastings
A1 Alvaro Gonzalez-Rajal
A1 Jeremy Z.R. Han
A1 Rachael A. McCloy
A1 Yolande E.I. O’Donnell
A1 Monica Phimmachanh
A1 Alexander D. Murphy
A1 Adnan Nagrial
A1 Dariush Daneshvar
A1 Venessa Chin
A1 D. Neil Watkins
A1 Andrew Burgess
A1 David R. Croucher
YR 2019
UL http://biorxiv.org/content/early/2019/09/20/775924.abstract
AB Identification of clinically viable strategies for overcoming resistance to platinum chemotherapy in lung adenocarcinoma has been hampered by inappropriately tailored in vitro assays of drug response. Therefore, using a pulse model that closely recapitulates the in vivo pharmacokinetics of platinum therapy, we profiled cisplatin-induced signalling, DNA damage and apoptotic responses across a panel of lung adenocarcinoma cell lines. By coupling this data with real-time, single cell imaging of cell cycle and apoptosis, we show that TP53 mutation status influenced the mode of cisplatin induced cell cycle arrest, but could not predict cisplatin sensitivity. In contrast, P70S6K-mediated signalling promoted resistance by increasing p53/p63 and p21 expression, reducing double-stranded DNA breaks and apoptosis. Targeting P70S6K sensitised both TP53 wildtype and null lines to cisplatin, but not TP53 mutant lines. In summary, using in vitro assays that mimic in vivo pharmacokinetics identified P70S6K as a robust mediator of cisplatin resistance and highlighted the importance of considering somatic mutation status when designing patient-specific combination therapies.