Acquired Resistance of EGFR-Mutated Lung Cancer to Tyrosine Kinase Inhibitor Treatment Promotes PARP Inhibitor Sensitivity
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Acquired Resistance of EGFR-Mutated Lung Cancer to Tyrosine Kinase Inhibitor Treatment Promotes PARP Inhibitor Sensitivity. / Marcar, Lynnette; Bardhan, Kankana; Gheorghiu, Liliana; Dinkelborg, Patrick; Pfäffle, Heike; Liu, Qi; Wang, Meng; Piotrowska, Zofia; Sequist, Lecia V; Borgmann, Kerstin; Settleman, Jeffrey E; Engelman, Jeffrey A; Hata, Aaron N; Willers, Henning.
in: CELL REP, Jahrgang 27, Nr. 12, 18.06.2019, S. 3422-3432.e4.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Acquired Resistance of EGFR-Mutated Lung Cancer to Tyrosine Kinase Inhibitor Treatment Promotes PARP Inhibitor Sensitivity
AU - Marcar, Lynnette
AU - Bardhan, Kankana
AU - Gheorghiu, Liliana
AU - Dinkelborg, Patrick
AU - Pfäffle, Heike
AU - Liu, Qi
AU - Wang, Meng
AU - Piotrowska, Zofia
AU - Sequist, Lecia V
AU - Borgmann, Kerstin
AU - Settleman, Jeffrey E
AU - Engelman, Jeffrey A
AU - Hata, Aaron N
AU - Willers, Henning
N1 - Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.
PY - 2019/6/18
Y1 - 2019/6/18
N2 - Lung cancers with oncogenic mutations in the epidermal growth factor receptor (EGFR) invariably acquire resistance to tyrosine kinase inhibitor (TKI) treatment. Vulnerabilities of EGFR TKI-resistant cancer cells that could be therapeutically exploited are incompletely understood. Here, we describe a poly (ADP-ribose) polymerase 1 (PARP-1) inhibitor-sensitive phenotype that is conferred by TKI treatment in vitro and in vivo and appears independent of any particular TKI resistance mechanism. We find that PARP-1 protects cells against cytotoxic reactive oxygen species (ROS) produced by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX). Compared to TKI-naive cells, TKI-resistant cells exhibit signs of increased RAC1 activity. PARP-1 catalytic function is required for PARylation of RAC1 at evolutionarily conserved sites in TKI-resistant cells, which restricts NOX-mediated ROS production. Our data identify a role of PARP-1 in controlling ROS levels upon EGFR TKI treatment, with potentially broad implications for therapeutic targeting of the mechanisms that govern the survival of oncogene-driven cancer cells.
AB - Lung cancers with oncogenic mutations in the epidermal growth factor receptor (EGFR) invariably acquire resistance to tyrosine kinase inhibitor (TKI) treatment. Vulnerabilities of EGFR TKI-resistant cancer cells that could be therapeutically exploited are incompletely understood. Here, we describe a poly (ADP-ribose) polymerase 1 (PARP-1) inhibitor-sensitive phenotype that is conferred by TKI treatment in vitro and in vivo and appears independent of any particular TKI resistance mechanism. We find that PARP-1 protects cells against cytotoxic reactive oxygen species (ROS) produced by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX). Compared to TKI-naive cells, TKI-resistant cells exhibit signs of increased RAC1 activity. PARP-1 catalytic function is required for PARylation of RAC1 at evolutionarily conserved sites in TKI-resistant cells, which restricts NOX-mediated ROS production. Our data identify a role of PARP-1 in controlling ROS levels upon EGFR TKI treatment, with potentially broad implications for therapeutic targeting of the mechanisms that govern the survival of oncogene-driven cancer cells.
U2 - 10.1016/j.celrep.2019.05.058
DO - 10.1016/j.celrep.2019.05.058
M3 - SCORING: Journal article
C2 - 31216465
VL - 27
SP - 3422-3432.e4
JO - CELL REP
JF - CELL REP
SN - 2211-1247
IS - 12
ER -