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Resistance to platinum chemotherapy in lung adenocarcinoma is driven by a non-genetic, cell-cycle dependent mechanism

Gonzalez-Rajal, A.; McCloy, R. A.; Nobis, M.; Marzec, K.; Chin, V.; Hastings, J. F.; Lai, K.; Kennerson, M.; Vaghjiani, V.; Hughes, W. E.; Timpson, P.; Cain, J.; Watkins, D. N.; Croucher, D. R.; Burgess, A.

2020-11-27 cell biology
10.1101/2020.11.26.400499 bioRxiv
Show 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 lung adenocarcinoma that is dependent on the cell cycle stage at the time of cisplatin exposure.

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