A non-genetic, cell cycle-dependent mechanism of platinum resistance in lung adenocarcinoma

Alvaro Gonzalez Rajal; Kamila A Marzec; Rachael A McCloy; Max Nobis; Venessa Chin; Jordan F Hastings; Kaitao Lai; Marina Kennerson; William E Hughes; Vijesh Vaghjiani; Paul Timpson; Jason E Cain; D Neil Watkins; David R Croucher; Andrew Burgess

doi:10.7554/eLife.65234

eLife (May 2021)

A non-genetic, cell cycle-dependent mechanism of platinum resistance in lung adenocarcinoma

Alvaro Gonzalez Rajal,
Kamila A Marzec,
Rachael A McCloy,
Max Nobis,
Venessa Chin,
Jordan F Hastings,
Kaitao Lai,
Marina Kennerson,
William E Hughes,
Vijesh Vaghjiani,
Paul Timpson,
Jason E Cain,
D Neil Watkins,
David R Croucher,
Andrew Burgess

Affiliations

Alvaro Gonzalez Rajal: ORCiD; 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
Kamila A Marzec: ORCiD; ANZAC Research Institute, Concord Hospital, Concord, Australia
Rachael A McCloy: The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, Australia
Max Nobis: ORCiD; 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
Jordan F Hastings: ORCiD; The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, Australia
Kaitao Lai: ORCiD; ANZAC Research Institute, Concord Hospital, Concord, Australia; The University of Sydney Concord Clinical School, Faculty of Medicine and Health, Sydney, Australia
Marina Kennerson: ORCiD; 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
Jason E Cain: ORCiD; Hudson Institute of Medical Research, Clayton, Australia; Department of Molecular and Translational Medicine, School of Medicine, Nursing and Health Sciences, Monash University, Clayton, Australia
D Neil Watkins: ORCiD; Research Institute in Oncology and Hematology, CancerCare Manitoba, Winnipeg, Canada; Department of Internal Medicine, Rady Faculty of Health Science, University of Manitoba, Winnipeg, Canada
David R Croucher: ORCiD; St Vincent's Hospital Clinical School, University of New South Wales, Sydney, Australia; The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, Australia
Andrew Burgess: ORCiD; ANZAC Research Institute, Concord Hospital, Concord, Australia

DOI: https://doi.org/10.7554/eLife.65234
Journal volume & issue: Vol. 10

Abstract

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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.

Published in eLife

ISSN: 2050-084X (Online)
Publisher: eLife Sciences Publications Ltd
Country of publisher: United Kingdom
LCC subjects: Medicine; Science: Biology (General)
Website: https://elifesciences.org

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