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

Alvaro Gonzalez RajalKamila A MarzecRachael A McCloyMax NobisVenessa ChinJordan F HastingsKaitao LaiMarina L KennersonWilliam E HughesVijesh VaghjianiPaul TimpsonJason E CainD Neil WatkinsDavid R CroucherAndrew Burgess
Published in: eLife (2021)
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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