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.
Highlights
Lung adenocarcinoma (LUAD) is the most common form of lung cancer and the leading cause of cancer-related death in Australia
We recently demonstrated that analysis of an in vitro assay that accurately models the in vivo drug exposure kinetics for cisplatin could provide therapeutically relevant insights into the signalling dynamics associated with innate resistance (Hastings et al, 2020)
In our previous work (Hastings et al, 2020), we identified several targetable signalling pathways that were associated with resistance to cisplatin in LUAD cells
Summary
Lung adenocarcinoma (LUAD) is the most common form of lung cancer and the leading cause of cancer-related death in Australia. Less than 15% of patients have a targetable driver mutation and cannot benefit from targeted therapy (Herbst et al, 2018). The overwhelming majority of LUAD patients receive platinum-based chemotherapy as standard of care. The antitumour abilities of platinum compounds were first identified over 50 years ago with the discovery of cisplatin (Kelland, 2007). Cisplatin and its derivatives have become one of the most successful groups of chemotherapeutics ever developed. Platinum therapy is essentially curative in testicular cancer, with survival rates > 90%, and is a frontline treatment for small-cell lung cancer, ovarian, head and neck, bladder, and cervical cancers (Gonzalez-Rajal et al, 2020; Kelland, 2007)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
