A non-genetic, cell cycle-dependent mechanism of platinum resistance in lung adenocarcinoma
Álvaro González-Rajal, Kamila A. Marzec, Rachael A. McCloy, Max Nobis, Venessa Chin, Jordan F. Hastings, Kaitao Lai, Marina Kennerson, William E. Hughes, Vijesh Vaghjiani, Paul Timpson, Jason E. Cain, D. Neil Watkins, David R. Croucher, Andrew Burgess
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.