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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, Vol. 27, No. 12, 18.06.2019, p. 3422-3432.e4.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Marcar, L, Bardhan, K, Gheorghiu, L, Dinkelborg, P, Pfäffle, H, Liu, Q, Wang, M, Piotrowska, Z, Sequist, LV, Borgmann, K, Settleman, JE, Engelman, JA, Hata, AN & Willers, H 2019, 'Acquired Resistance of EGFR-Mutated Lung Cancer to Tyrosine Kinase Inhibitor Treatment Promotes PARP Inhibitor Sensitivity', CELL REP, vol. 27, no. 12, pp. 3422-3432.e4. https://doi.org/10.1016/j.celrep.2019.05.058

APA

Marcar, L., Bardhan, K., Gheorghiu, L., Dinkelborg, P., Pfäffle, H., Liu, Q., Wang, M., Piotrowska, Z., Sequist, L. V., Borgmann, K., Settleman, J. E., Engelman, J. A., Hata, A. N., & Willers, H. (2019). Acquired Resistance of EGFR-Mutated Lung Cancer to Tyrosine Kinase Inhibitor Treatment Promotes PARP Inhibitor Sensitivity. CELL REP, 27(12), 3422-3432.e4. https://doi.org/10.1016/j.celrep.2019.05.058

Vancouver

Marcar L, Bardhan K, Gheorghiu L, Dinkelborg P, Pfäffle H, Liu Q et al. Acquired Resistance of EGFR-Mutated Lung Cancer to Tyrosine Kinase Inhibitor Treatment Promotes PARP Inhibitor Sensitivity. CELL REP. 2019 Jun 18;27(12):3422-3432.e4. https://doi.org/10.1016/j.celrep.2019.05.058

Bibtex

@article{aa8c9dbdb32140c6b4d0c09d17202f6b,
title = "Acquired Resistance of EGFR-Mutated Lung Cancer to Tyrosine Kinase Inhibitor Treatment Promotes PARP Inhibitor Sensitivity",
abstract = "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.",
author = "Lynnette Marcar and Kankana Bardhan and Liliana Gheorghiu and Patrick Dinkelborg and Heike Pf{\"a}ffle and Qi Liu and Meng Wang and Zofia Piotrowska and Sequist, {Lecia V} and Kerstin Borgmann and Settleman, {Jeffrey E} and Engelman, {Jeffrey A} and Hata, {Aaron N} and Henning Willers",
note = "Copyright {\textcopyright} 2019 The Author(s). Published by Elsevier Inc. All rights reserved.",
year = "2019",
month = jun,
day = "18",
doi = "10.1016/j.celrep.2019.05.058",
language = "English",
volume = "27",
pages = "3422--3432.e4",
journal = "CELL REP",
issn = "2211-1247",
publisher = "Elsevier",
number = "12",

}

RIS

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 -