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bioRxiv · 10.1101/2020.11.26.400499

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.
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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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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. Resistance to platinum chemotherapy in lung adenocarcinoma is driven by a non-genetic, cell-cycle dependent mechanism. https://doi.org/10.1101/2020.11.26.400499

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