Nucleotide excision repair is a potential therapeutic target in multiple myeloma

R. Szalat, M. K. Samur, M. Fulciniti, M. Lopez, P. Nanjappa, A. Cleynen, K. Wen, Shaji K Kumar, T. Perini, A. S. Calkins, E. Reznichenko, D. Chauhan, Y. T. Tai, M. A. Shammas, K. C. Anderson, J. P. Fermand, B. Arnulf, H. Avet-Loiseau, J. B. Lazaro, N. C. Munshi

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Despite the development of novel drugs, alkylating agents remain an important component of therapy in multiple myeloma (MM). DNA repair processes contribute towards sensitivity to alkylating agents and therefore we here evaluate the role of nucleotide excision repair (NER), which is involved in the removal of bulky adducts and DNA crosslinks in MM. We first evaluated NER activity using a novel functional assay and observed a heterogeneous NER efficiency in MM cell lines and patient samples. Using nextgeneration sequencing data, we identified that expression of the canonical NER gene, excision repair cross-complementation group 3 (ERCC3), significantly impacted the outcome in newly diagnosed MM patients treated with alkylating agents. Next, using small RNA interference, stable knockdown and overexpression, and small-molecule inhibitors targeting xeroderma pigmentosum complementation group B (XPB), the DNA helicase encoded by ERCC3, we demonstrate that NER inhibition significantly increases sensitivity and overcomes resistance to alkylating agents in MM. Moreover, inhibiting XPB leads to the dual inhibition of NER and transcription and is particularly efficient in myeloma cells. Altogether, we show that NER impacts alkylating agents sensitivity in myeloma cells and identify ERCC3 as a potential therapeutic target in MM.

Original languageEnglish (US)
Pages (from-to)111-119
Number of pages9
JournalLeukemia
Volume32
Issue number1
DOIs
StatePublished - Jan 1 2018
Externally publishedYes

Fingerprint

Multiple Myeloma
DNA Repair
Alkylating Agents
Therapeutics
DNA Helicases
DNA Adducts
RNA Interference
Cell Line

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

Cite this

Szalat, R., Samur, M. K., Fulciniti, M., Lopez, M., Nanjappa, P., Cleynen, A., ... Munshi, N. C. (2018). Nucleotide excision repair is a potential therapeutic target in multiple myeloma. Leukemia, 32(1), 111-119. https://doi.org/10.1038/leu.2017.182

Nucleotide excision repair is a potential therapeutic target in multiple myeloma. / Szalat, R.; Samur, M. K.; Fulciniti, M.; Lopez, M.; Nanjappa, P.; Cleynen, A.; Wen, K.; Kumar, Shaji K; Perini, T.; Calkins, A. S.; Reznichenko, E.; Chauhan, D.; Tai, Y. T.; Shammas, M. A.; Anderson, K. C.; Fermand, J. P.; Arnulf, B.; Avet-Loiseau, H.; Lazaro, J. B.; Munshi, N. C.

In: Leukemia, Vol. 32, No. 1, 01.01.2018, p. 111-119.

Research output: Contribution to journalArticle

Szalat, R, Samur, MK, Fulciniti, M, Lopez, M, Nanjappa, P, Cleynen, A, Wen, K, Kumar, SK, Perini, T, Calkins, AS, Reznichenko, E, Chauhan, D, Tai, YT, Shammas, MA, Anderson, KC, Fermand, JP, Arnulf, B, Avet-Loiseau, H, Lazaro, JB & Munshi, NC 2018, 'Nucleotide excision repair is a potential therapeutic target in multiple myeloma', Leukemia, vol. 32, no. 1, pp. 111-119. https://doi.org/10.1038/leu.2017.182
Szalat R, Samur MK, Fulciniti M, Lopez M, Nanjappa P, Cleynen A et al. Nucleotide excision repair is a potential therapeutic target in multiple myeloma. Leukemia. 2018 Jan 1;32(1):111-119. https://doi.org/10.1038/leu.2017.182
Szalat, R. ; Samur, M. K. ; Fulciniti, M. ; Lopez, M. ; Nanjappa, P. ; Cleynen, A. ; Wen, K. ; Kumar, Shaji K ; Perini, T. ; Calkins, A. S. ; Reznichenko, E. ; Chauhan, D. ; Tai, Y. T. ; Shammas, M. A. ; Anderson, K. C. ; Fermand, J. P. ; Arnulf, B. ; Avet-Loiseau, H. ; Lazaro, J. B. ; Munshi, N. C. / Nucleotide excision repair is a potential therapeutic target in multiple myeloma. In: Leukemia. 2018 ; Vol. 32, No. 1. pp. 111-119.
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