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

Alvaro Gonzalez 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

doi:10.7554/eLife.65234

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

Elife. 2021 May 13:10:e65234. doi: 10.7554/eLife.65234.

Authors

Alvaro Gonzalez Rajal^{1

2

3}, Kamila A Marzec¹, Rachael A McCloy⁴, Max Nobis^{3

4}, Venessa Chin^{3

4

5}, Jordan F Hastings⁴, Kaitao Lai^{1

6}, Marina Kennerson^{1

6}, William E Hughes^{2

3

7}, Vijesh Vaghjiani⁸, Paul Timpson^{3

4}, Jason E Cain^{8

9}, D Neil Watkins^{10

11}, David R Croucher^#^{3

4}, Andrew Burgess^#¹

Affiliations

¹ ANZAC Research Institute, Concord Hospital, Concord, Australia.
² Garvan Institute of Medical Research, Sydney, Australia.
³ St Vincent's Hospital Clinical School, University of New South Wales, Sydney, Australia.
⁴ The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, Australia.
⁵ St Vincent's Hospital Sydney, Darlinghurst, Australia.
⁶ The University of Sydney Concord Clinical School, Faculty of Medicine and Health, Sydney, Australia.
⁷ Children's Medical Research Institute, The University of Sydney, Westmead, Australia.
⁸ Hudson Institute of Medical Research, Clayton, Australia.
⁹ Department of Molecular and Translational Medicine, School of Medicine, Nursing and Health Sciences, Monash University, Clayton, Australia.
¹⁰ Research Institute in Oncology and Hematology, CancerCare Manitoba, Winnipeg, Canada.
¹¹ Department of Internal Medicine, Rady Faculty of Health Science, University of Manitoba, Winnipeg, Canada.

^# Contributed equally.

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.

Keywords: 53BP1; BRCA1; DNA repair; PARP1; cancer biology; cell biology; cell cycle; human; mitosis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenocarcinoma of Lung / metabolism
Adenocarcinoma of Lung / pathology*
Animals
Antineoplastic Agents / pharmacology*
Carboplatin / pharmacology*
Cell Line, Tumor
Cisplatin / pharmacology*
DNA Damage / drug effects
Drug Resistance, Neoplasm*
Humans
Lung Neoplasms / metabolism
Lung Neoplasms / pathology*
Mice
Poly(ADP-ribose) Polymerase Inhibitors
Rad51 Recombinase
Single-Cell Analysis
Xenograft Model Antitumor Assays

Substances

Antineoplastic Agents
Poly(ADP-ribose) Polymerase Inhibitors
Carboplatin
Rad51 Recombinase
Cisplatin

Associated data

GEO/GSE161800

Grants and funding

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.