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Molecular mechanisms of cisplatin resistance

Abstract

Platinum-based drugs, and in particular cis-diamminedichloroplatinum(II) (best known as cisplatin), are employed for the treatment of a wide array of solid malignancies, including testicular, ovarian, head and neck, colorectal, bladder and lung cancers. Cisplatin exerts anticancer effects via multiple mechanisms, yet its most prominent (and best understood) mode of action involves the generation of DNA lesions followed by the activation of the DNA damage response and the induction of mitochondrial apoptosis. Despite a consistent rate of initial responses, cisplatin treatment often results in the development of chemoresistance, leading to therapeutic failure. An intense research has been conducted during the past 30 years and several mechanisms that account for the cisplatin-resistant phenotype of tumor cells have been described. Here, we provide a systematic discussion of these mechanism by classifying them in alterations (1) that involve steps preceding the binding of cisplatin to DNA (pre-target resistance), (2) that directly relate to DNA–cisplatin adducts (on-target resistance), (3) concerning the lethal signaling pathway(s) elicited by cisplatin-mediated DNA damage (post-target resistance) and (4) affecting molecular circuitries that do not present obvious links with cisplatin-elicited signals (off-target resistance). As in some clinical settings cisplatin constitutes the major therapeutic option, the development of chemosensitization strategies constitute a goal with important clinical implications.

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Abbreviations

ABC:

ATP-binding cassette

ATM:

ataxia telangiectasia mutated

ATR:

ATM- and RAD3-related

BCL-2:

B-cell lymphoma 2

CDKN1A:

cyclin-dependent kinase inhibitor 1A

CHEK:

checkpoint kinase

CTR1:

copper transporter 1

DYRK1B:

dual-specificity Y-phosphorylation regulated kinase 1B

ERCC:

excision repair cross-complementing rodent repair deficiency

GSH:

reduced glutathione

HR:

homologous recombination

ICR:

interstrand crosslink repair

MAPK:

mitogen-activated protein kinase

MMR:

mismatch repair

MRP:

multidrug resistance protein

NER:

nucleotide excision repair

NSCLC:

non-small cell lung cancer

PI3K:

phosphoinositide-3-kinase

RRM2B:

ribonucleotide reductase M2 B

VDAC:

voltage-dependent anion channel

XAF1:

XIAP-associated factor 1

XPF:

xeroderma pigmentosum complementation group F

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Acknowledgements

LG and LS are supported by the European Commission (Apo-Sys) and the Fondation pour la Recherche Médicale (FRM), respectively. IV is funded by the Ligue Nationale contre le Cancer. GK is supported by Ligue Nationale contre le Cancer (équipe labellisée), AXA Chair for Longevity Research, Cancéropôle Ile-de-France, Institut National du Cancer (INCa), Fondation Bettencourt-Schueller, Fondation de France, FRM, Agence National de la Recherche, LabEx Immuno-Oncology and the European Commission (Apo-Sys, ArtForce, ChemoRes. Death-Train).

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Galluzzi, L., Senovilla, L., Vitale, I. et al. Molecular mechanisms of cisplatin resistance. Oncogene 31, 1869–1883 (2012). https://doi.org/10.1038/onc.2011.384

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