ANZAC Research Institute, Concord Hospital, Concord, Australia; Garvan Institute of Medical Research, Sydney, Australia; St Vincent's Hospital Clinical School, University of New South Wales, Sydney, Australia
St Vincent's Hospital Clinical School, University of New South Wales, Sydney, Australia; The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, Australia
Venessa Chin
St Vincent's Hospital Clinical School, University of New South Wales, Sydney, Australia; The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, Australia; St Vincent’s Hospital Sydney, Darlinghurst, Australia
ANZAC Research Institute, Concord Hospital, Concord, Australia; The University of Sydney Concord Clinical School, Faculty of Medicine and Health, Sydney, Australia
ANZAC Research Institute, Concord Hospital, Concord, Australia; The University of Sydney Concord Clinical School, Faculty of Medicine and Health, Sydney, Australia
William E Hughes
Garvan Institute of Medical Research, Sydney, Australia; St Vincent's Hospital Clinical School, University of New South Wales, Sydney, Australia; Children’s Medical Research Institute, The University of Sydney, Westmead, Australia
Vijesh Vaghjiani
Hudson Institute of Medical Research, Clayton, Australia
Paul Timpson
St Vincent's Hospital Clinical School, University of New South Wales, Sydney, Australia; The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, Australia
Hudson Institute of Medical Research, Clayton, Australia; Department of Molecular and Translational Medicine, School of Medicine, Nursing and Health Sciences, Monash University, Clayton, Australia
Research Institute in Oncology and Hematology, CancerCare Manitoba, Winnipeg, Canada; Department of Internal Medicine, Rady Faculty of Health Science, University of Manitoba, Winnipeg, Canada
St Vincent's Hospital Clinical School, University of New South Wales, Sydney, Australia; The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, Australia
We previously used a pulse-based in vitro assay to unveil targetable signalling pathways associated with innate cisplatin resistance in lung adenocarcinoma (Hastings et al., 2020). Here, we advanced this model system and identified a non-genetic mechanism of resistance that drives recovery and regrowth in a subset of cells. Using RNAseq and a suite of biosensors to track single-cell fates both in vitro and in vivo, we identified that early S phase cells have a greater ability to maintain proliferative capacity, which correlated with reduced DNA damage over multiple generations. In contrast, cells in G1, late S or those treated with PARP/RAD51 inhibitors, maintained higher levels of DNA damage and underwent prolonged S/G2 phase arrest and senescence. Combined with our previous work, these data indicate that there is a non-genetic mechanism of resistance in human lung adenocarcinoma that is dependent on the cell cycle stage at the time of cisplatin exposure.
