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Identification of a Synthetic Lethal Relationship between Nucleotide Excision Repair Deficiency and Irofulven Sensitivity in Urothelial Cancer

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Harvard

Börcsök, J, Sztupinszki, Z, Bekele, R, Gao, SP, Diossy, M, Samant, AS, Dillon, KM, Tisza, V, Spisák, S, Rusz, O, Csabai, I, Pappot, H, Frazier, ZJ, Konieczkowski, DJ, Liu, D, Vasani, N, Rodrigues, JA, Solit, DB, Hoffman-Censits, JH, Plimack, ER, Rosenberg, JE, Lazaro, J-B, Taplin, M-E, Iyer, G, Brunak, S, Lozsa, R, Van Allen, EM, Szüts, D, Mouw, KW & Szallasi, Z 2021, 'Identification of a Synthetic Lethal Relationship between Nucleotide Excision Repair Deficiency and Irofulven Sensitivity in Urothelial Cancer', Clinical Cancer Research, vol. 27, no. 7, pp. 2011-2022. https://doi.org/10.1158/1078-0432.CCR-20-3316

APA

Börcsök, J., Sztupinszki, Z., Bekele, R., Gao, S. P., Diossy, M., Samant, A. S., Dillon, K. M., Tisza, V., Spisák, S., Rusz, O., Csabai, I., Pappot, H., Frazier, Z. J., Konieczkowski, D. J., Liu, D., Vasani, N., Rodrigues, J. A., Solit, D. B., Hoffman-Censits, J. H., ... Szallasi, Z. (2021). Identification of a Synthetic Lethal Relationship between Nucleotide Excision Repair Deficiency and Irofulven Sensitivity in Urothelial Cancer. Clinical Cancer Research, 27(7), 2011-2022. https://doi.org/10.1158/1078-0432.CCR-20-3316

CBE

Börcsök J, Sztupinszki Z, Bekele R, Gao SP, Diossy M, Samant AS, Dillon KM, Tisza V, Spisák S, Rusz O, Csabai I, Pappot H, Frazier ZJ, Konieczkowski DJ, Liu D, Vasani N, Rodrigues JA, Solit DB, Hoffman-Censits JH, Plimack ER, Rosenberg JE, Lazaro J-B, Taplin M-E, Iyer G, Brunak S, Lozsa R, Van Allen EM, Szüts D, Mouw KW, Szallasi Z. 2021. Identification of a Synthetic Lethal Relationship between Nucleotide Excision Repair Deficiency and Irofulven Sensitivity in Urothelial Cancer. Clinical Cancer Research. 27(7):2011-2022. https://doi.org/10.1158/1078-0432.CCR-20-3316

MLA

Vancouver

Author

Börcsök, Judit ; Sztupinszki, Zsofia ; Bekele, Raie ; Gao, Sizhi P ; Diossy, Miklos ; Samant, Amruta S ; Dillon, Kasia M ; Tisza, Viktoria ; Spisák, Sándor ; Rusz, Orsolya ; Csabai, Istvan ; Pappot, Helle ; Frazier, Zoe J ; Konieczkowski, David J ; Liu, David ; Vasani, Naresh ; Rodrigues, James A ; Solit, David B ; Hoffman-Censits, Jean H ; Plimack, Elizabeth R ; Rosenberg, Jonathan E ; Lazaro, Jean-Bernard ; Taplin, Mary-Ellen ; Iyer, Gopa ; Brunak, Søren ; Lozsa, Rita ; Van Allen, Eliezer M ; Szüts, Dávid ; Mouw, Kent W ; Szallasi, Zoltan. / Identification of a Synthetic Lethal Relationship between Nucleotide Excision Repair Deficiency and Irofulven Sensitivity in Urothelial Cancer. In: Clinical Cancer Research. 2021 ; Vol. 27, No. 7. pp. 2011-2022.

Bibtex

@article{cb2f5d6162bd41bfb9562d5fee03d9e8,
title = "Identification of a Synthetic Lethal Relationship between Nucleotide Excision Repair Deficiency and Irofulven Sensitivity in Urothelial Cancer",
abstract = "PURPOSE: Cisplatin-based chemotherapy is a first-line treatment for muscle-invasive and metastatic urothelial cancer. Approximately 10% of bladder urothelial tumors have a somatic missense mutation in the nucleotide excision repair (NER) gene, ERCC2, which confers increased sensitivity to cisplatin-based chemotherapy. However, a significant subset of patients is ineligible to receive cisplatin-based therapy due to medical contraindications, and no NER-targeted approaches are available for platinum-ineligible or platinum-refractory ERCC2-mutant cases. EXPERIMENTAL DESIGN: We used a series of NER-proficient and NER-deficient preclinical tumor models to test sensitivity to irofulven, an abandoned anticancer agent. In addition, we used available clinical and sequencing data from multiple urothelial tumor cohorts to develop and validate a composite mutational signature of ERCC2 deficiency and cisplatin sensitivity. RESULTS: We identified a novel synthetic lethal relationship between tumor NER deficiency and sensitivity to irofulven. Irofulven specifically targets cells with inactivation of the transcription-coupled NER (TC-NER) pathway and leads to robust responses in vitro and in vivo, including in models with acquired cisplatin resistance, while having minimal effect on cells with intact NER. We also found that a composite mutational signature of ERCC2 deficiency was strongly associated with cisplatin response in patients and was also associated with cisplatin and irofulven sensitivity in preclinical models. CONCLUSIONS: Tumor NER deficiency confers sensitivity to irofulven, a previously abandoned anticancer agent, with minimal activity in NER-proficient cells. A composite mutational signature of NER deficiency may be useful in identifying patients likely to respond to NER-targeting agents, including cisplatin and irofulven.",
author = "Judit B{\"o}rcs{\"o}k and Zsofia Sztupinszki and Raie Bekele and Gao, {Sizhi P} and Miklos Diossy and Samant, {Amruta S} and Dillon, {Kasia M} and Viktoria Tisza and S{\'a}ndor Spis{\'a}k and Orsolya Rusz and Istvan Csabai and Helle Pappot and Frazier, {Zoe J} and Konieczkowski, {David J} and David Liu and Naresh Vasani and Rodrigues, {James A} and Solit, {David B} and Hoffman-Censits, {Jean H} and Plimack, {Elizabeth R} and Rosenberg, {Jonathan E} and Jean-Bernard Lazaro and Mary-Ellen Taplin and Gopa Iyer and S{\o}ren Brunak and Rita Lozsa and {Van Allen}, {Eliezer M} and D{\'a}vid Sz{\"u}ts and Mouw, {Kent W} and Zoltan Szallasi",
note = "{\textcopyright}2020 American Association for Cancer Research.",
year = "2021",
month = apr,
day = "1",
doi = "10.1158/1078-0432.CCR-20-3316",
language = "English",
volume = "27",
pages = "2011--2022",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research (A A C R)",
number = "7",

}

RIS

TY - JOUR

T1 - Identification of a Synthetic Lethal Relationship between Nucleotide Excision Repair Deficiency and Irofulven Sensitivity in Urothelial Cancer

AU - Börcsök, Judit

AU - Sztupinszki, Zsofia

AU - Bekele, Raie

AU - Gao, Sizhi P

AU - Diossy, Miklos

AU - Samant, Amruta S

AU - Dillon, Kasia M

AU - Tisza, Viktoria

AU - Spisák, Sándor

AU - Rusz, Orsolya

AU - Csabai, Istvan

AU - Pappot, Helle

AU - Frazier, Zoe J

AU - Konieczkowski, David J

AU - Liu, David

AU - Vasani, Naresh

AU - Rodrigues, James A

AU - Solit, David B

AU - Hoffman-Censits, Jean H

AU - Plimack, Elizabeth R

AU - Rosenberg, Jonathan E

AU - Lazaro, Jean-Bernard

AU - Taplin, Mary-Ellen

AU - Iyer, Gopa

AU - Brunak, Søren

AU - Lozsa, Rita

AU - Van Allen, Eliezer M

AU - Szüts, Dávid

AU - Mouw, Kent W

AU - Szallasi, Zoltan

N1 - ©2020 American Association for Cancer Research.

PY - 2021/4/1

Y1 - 2021/4/1

N2 - PURPOSE: Cisplatin-based chemotherapy is a first-line treatment for muscle-invasive and metastatic urothelial cancer. Approximately 10% of bladder urothelial tumors have a somatic missense mutation in the nucleotide excision repair (NER) gene, ERCC2, which confers increased sensitivity to cisplatin-based chemotherapy. However, a significant subset of patients is ineligible to receive cisplatin-based therapy due to medical contraindications, and no NER-targeted approaches are available for platinum-ineligible or platinum-refractory ERCC2-mutant cases. EXPERIMENTAL DESIGN: We used a series of NER-proficient and NER-deficient preclinical tumor models to test sensitivity to irofulven, an abandoned anticancer agent. In addition, we used available clinical and sequencing data from multiple urothelial tumor cohorts to develop and validate a composite mutational signature of ERCC2 deficiency and cisplatin sensitivity. RESULTS: We identified a novel synthetic lethal relationship between tumor NER deficiency and sensitivity to irofulven. Irofulven specifically targets cells with inactivation of the transcription-coupled NER (TC-NER) pathway and leads to robust responses in vitro and in vivo, including in models with acquired cisplatin resistance, while having minimal effect on cells with intact NER. We also found that a composite mutational signature of ERCC2 deficiency was strongly associated with cisplatin response in patients and was also associated with cisplatin and irofulven sensitivity in preclinical models. CONCLUSIONS: Tumor NER deficiency confers sensitivity to irofulven, a previously abandoned anticancer agent, with minimal activity in NER-proficient cells. A composite mutational signature of NER deficiency may be useful in identifying patients likely to respond to NER-targeting agents, including cisplatin and irofulven.

AB - PURPOSE: Cisplatin-based chemotherapy is a first-line treatment for muscle-invasive and metastatic urothelial cancer. Approximately 10% of bladder urothelial tumors have a somatic missense mutation in the nucleotide excision repair (NER) gene, ERCC2, which confers increased sensitivity to cisplatin-based chemotherapy. However, a significant subset of patients is ineligible to receive cisplatin-based therapy due to medical contraindications, and no NER-targeted approaches are available for platinum-ineligible or platinum-refractory ERCC2-mutant cases. EXPERIMENTAL DESIGN: We used a series of NER-proficient and NER-deficient preclinical tumor models to test sensitivity to irofulven, an abandoned anticancer agent. In addition, we used available clinical and sequencing data from multiple urothelial tumor cohorts to develop and validate a composite mutational signature of ERCC2 deficiency and cisplatin sensitivity. RESULTS: We identified a novel synthetic lethal relationship between tumor NER deficiency and sensitivity to irofulven. Irofulven specifically targets cells with inactivation of the transcription-coupled NER (TC-NER) pathway and leads to robust responses in vitro and in vivo, including in models with acquired cisplatin resistance, while having minimal effect on cells with intact NER. We also found that a composite mutational signature of ERCC2 deficiency was strongly associated with cisplatin response in patients and was also associated with cisplatin and irofulven sensitivity in preclinical models. CONCLUSIONS: Tumor NER deficiency confers sensitivity to irofulven, a previously abandoned anticancer agent, with minimal activity in NER-proficient cells. A composite mutational signature of NER deficiency may be useful in identifying patients likely to respond to NER-targeting agents, including cisplatin and irofulven.

UR - http://www.scopus.com/inward/record.url?scp=85104865661&partnerID=8YFLogxK

U2 - 10.1158/1078-0432.CCR-20-3316

DO - 10.1158/1078-0432.CCR-20-3316

M3 - Journal article

C2 - 33208343

VL - 27

SP - 2011

EP - 2022

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 7

ER -

ID: 61758605