Analysis of pulsed cisplatin signalling dynamics identifies effectors of resistance in lung adenocarcinoma

• DOI: 10.7554/elife.53367
• Publication Date: 2020-06-09T00:00:20Z
• Authors: Jordan F Hastings; Alvaro Gonzalez R...; 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
• Keywords: p53; Lung Neoplasms; QH301-705.5; Science; Adenocarcinoma of Lung; Antineoplastic Agents; Apoptosis; P70S6K; 03 medical and health sciences; Cell Line, Tumor; Humans; Biology (General); Cancer Biology; 0303 health sciences; Q; Cell Cycle; R; chemoresistance; lung adenocarcinoma; platinum chemotherapy; signalling dynamics; 3. Good health; Drug Resistance, Neoplasm; Medicine; Cisplatin; Signal Transduction

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.