Abstract
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.
Highlights
Lung adenocarcinoma is the most common form of lung cancer, the leading cause of cancer-related death worldwide
In order to directly compare the response of lung adenocarcinoma cells to the continuous presence of cisplatin, or a pulse of cisplatin that mimics in vivo pharmacokinetics (2 hr, 5 mg/mL) (Figure 1— figure supplement 1A), we monitored the growth and apoptosis of the innately resistant A549 lung adenocarcinoma cell line (Marini et al, 2018) by both live cell imaging (Figure 1—figure supplement 1B) and a cell viability assay (Figure 1—figure supplement 1C), under both conditions
This heightened DNA damage response during the continuous exposure to cisplatin was reflected in the increased activation of Caspase 3, which was completely absent for the pulse model
Summary
Lung adenocarcinoma is the most common form of lung cancer, the leading cause of cancer-related death worldwide. Gonzalez-Rajal et al developed a laboratory method that mimics the way cells are exposed to platinum-based chemotherapy in the body These experiments showed that the lung adenocarcinoma cells which resisted treatment carried high levels of a protein known as P70S6K. Pairing platinum-based chemotherapy with a drug that blocks the activity of P70S6K killed these resistant cells This combination treated human lung adenocarcinoma tumours growing under the skin of mice. In vitro methods for the investigation of drug response have involved culturing cancer cells in the continuous presence of high-dose chemotherapy over several days This contrasts with pharmacokinetic studies in humans and rodents demonstrating that both cisplatin and carboplatin are rapidly cleared from the circulation, and the tumour, within 2–3 hr following administration (Andersson et al, 1996; Johansen et al, 2002). We propose a therapeutic strategy targeting P70S6K using the dual PI3K/mTOR inhibitor dactolisib, with the potential to improve the efficacy of current platinum-based treatment regimens
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