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

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 regro...

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Published in:eLife Vol. 10
Main Authors: Gonzalez Rajal, Alvaro, Marzec, Kamila A, McCloy, Rachael A, Nobis, Max, Chin, Venessa, Hastings, Jordan F, Lai, Kaitao, Kennerson, Marina, Hughes, William E, Vaghjiani, Vijesh, Timpson, Paul, Cain, Jason E, Watkins, D Neil, Croucher, David R, Burgess, Andrew
Format: Journal Article
Language:English
Published: England eLife Science Publications, Ltd 13.05.2021
eLife Sciences Publications Ltd
eLife Sciences Publications, Ltd
Subjects:
53BP1
Adenocarcinoma
Biosensors
BRCA1
Cancer Biology
Cancer therapies
Carboplatin
Cell Biology
Cell cycle
Cisplatin
Cyclin-dependent kinases
Deoxyribonucleic acid
DNA
DNA damage
DNA repair
Flow cytometry
G2 phase
Kinases
Lung cancer
mitosis
Ovaries
PARP1
Poly(ADP-ribose) polymerase
Research Advance
S phase
Senescence
Signal transduction
Testicular cancer
Fiji
human
cancer biology
cell biology
ISSN:2050-084X, 2050-084X
Online Access:Get full text
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Summary: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.
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These authors contributed equally to this work.
ISSN:2050-084X
2050-084X
DOI:10.7554/eLife.65234