MS CETSA deep functional proteomics uncovers DNA repair programs leading to gemcitabine resistance

Ying Yu Liang, Khalidah Khalid, Hai Van Le, Hui Min Vivian Teo, Mindaugas Raitelaitis, Marc-Antoine Gerault, Jane Jia Hui Lee, Jiawen Lyu, Allison Chan, Anand Devaprasath Jeyasekharan, Wai Leong Tam (), Pär Nordlund () and Nayana Prabhu ()
Additional contact information
Ying Yu Liang: 61 Biopolis Drive
Khalidah Khalid: 61 Biopolis Drive
Hai Van Le: 61 Biopolis Drive
Hui Min Vivian Teo: 60 Biopolis Street
Mindaugas Raitelaitis: Karolinska Institutet
Marc-Antoine Gerault: Karolinska Institutet
Jane Jia Hui Lee: 60 Biopolis Street
Jiawen Lyu: Karolinska Institutet
Allison Chan: National University of Singapore
Anand Devaprasath Jeyasekharan: National University of Singapore
Wai Leong Tam: Karolinska Institutet
Pär Nordlund: 61 Biopolis Drive
Nayana Prabhu: 61 Biopolis Drive

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: Abstract Mechanisms for resistance to cytotoxic cancer drugs are dependent on dynamic changes in the biochemistry of cellular pathways, information which is hard to obtain at the systems level. Here we use a deep functional proteomics implementation of the Cellular Thermal Shift Assay to reveal a range of induced biochemical responses to gemcitabine in resistant and sensitive diffuse large B cell lymphoma cell lines. Initial responses in both, gemcitabine resistant and sensitive cells, reflect known targeted effects by gemcitabine on ribonucleotide reductase and DNA damage responses. However, later responses diverge dramatically where sensitive cells show induction of characteristic CETSA signals for early apoptosis, while resistant cells reveal biochemical modulations reflecting transition through a distinct DNA-damage signaling state, including opening of cell cycle checkpoints and induction of translesion DNA synthesis programs, allowing bypass of damaged DNA-adducts. The results also show the induction of a protein ensemble, labeled the Auxiliary DNA Damage Repair, likely supporting DNA replication at damaged sites that can be attenuated in resistant cells by an ATR inhibitor, thus re-establishing gemcitabine sensitivity and demonstrating ATR as a key signaling node of this response.

Date: 2025
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DOI: 10.1038/s41467-025-59505-8

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