A non-genetic, cell cycle dependent mechanism of platinum resistance in lung adenocarcinoma
- Garvan Institute of Medical Research, Australia
- University of Sydney, Australia
- Children's Medical Research Institute, Australia
- Hudson Institute of Medical Research, Australia
- Research Institute in Oncology and Hematology, Canada
Abstract
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.
Data availability
Raw RNAseq data has been uploaded to the NCBI Gene Expression Omnibus (GEO) data repository with the accession number GSE161800.
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Pulsed cisplatin treatment of A549 lung adenocarcinoma cellsNCBI Gene Expression Omnibus, GSE161800.
Article and author information
Author details
Funding
National Breast Cancer Foundation (IIRS-18-103)
- Andrew Burgess
Tour de Cure (RSP-230-2020)
- Andrew Burgess
Cancer Institute NSW (10/FRL/3-02)
- Andrew Burgess
Cancer Institute NSW (2013/FRL102)
- David R Croucher
Cancer Institute NSW (15/REG/1-17)
- David R Croucher
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All experiments were carried out in compliance with the Australian code for the care and use of animals for scientific purposes and in compliance with Garvan Institute of Medical Research/St. Vincent's Hospital Animal Ethics Committee guidelines (ARA_18_17, ARA_16_13).
Reviewing Editor
- Maureen E Murphy, The Wistar Institute, United States
Publication history
- Received: December 1, 2020
- Accepted: May 11, 2021
- Accepted Manuscript published: May 13, 2021 (version 1)
- Version of Record published: May 31, 2021 (version 2)
- Version of Record updated: June 7, 2021 (version 3)
Copyright
© 2021, Gonzalez Rajal et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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A non-genetic, cell cycle dependent mechanism of platinum resistance in lung adenocarcinoma
eLife 10:e65234.
https://doi.org/10.7554/eLife.65234
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