Lung adenocarcinoma is the most prevalent lung cancer subtype and accounts for 40% of total cases. Platinum-based chemotherapy is the standard of care and although is initially effective the tumour becomes resistant in most cases and relapses, leading to therapeutic failure and patient death. Understanding lung adenocarcinoma's innate resistance to platinum would allow us to find new molecular targets that could be used in combined therapies to increase successful responses rates.
We have developed an in vitro model where lung adenocarcinoma cells are treated with cisplatin in a way that closely resembles its pharmacokinetic properties in solid tumours in vivo. Responses in a variety of cell lines was measured by analysing cell growth, cell cycle and population dynamics with live imaging, FACS and lineage tracing.
Cell lines responded with sustained cell cycle arrest, but little cell death, that persisted for days after a 2-hour pulse treatment with cisplatin. This was associated with a marked increase in nuclear and cell size and polyploidy. At the same time a small minority of cells are able to “escape” the treatment and regenerate the cell line with a phenotype identical to untreated cells. Remarkably, this pattern of response was preserved despite multiple challenges with cisplatin. Results using stable FUCCI (Fluorescence Ubiquitination Cell Cycle Indicator) cell lines suggest that heterogeneity in the effects of cisplatin is partially cell cycle dependent. We are currently analysing DNA repair responses by live imaging in order to elucidate their contribution in the process and performing in vivo studies in mouse to confirm our in vitro results.
These data suggest platinum resistance in lung adenocarcinoma in vivo is the result of deterministic phenotypic heterogeneity rather genetic Darwinian selection. This phenotypic heterogeneity can be partially explained as cell cycle dependent. Lack of response to cisplatin-based chemotherapy may be the result of tumour regeneration rather innate resistance within all cells of the tumour.