A functional cancer genomics screen identifies a druggable synthetic lethal interaction between MSH3 and PRKDC

Felix Dietlein, Lisa Thelen, Mladen Jokic, Ron D. Jachimowicz, Laura Ivan, Gero Knittel, Uschi Leeser, Johanna van Oers, Winfried Edelmann, Lukas C. Heukamp, H. Christian Reinhardt

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

Here, we use a large-scale cell line-based approach to identify cancer cell-specific mutations that are associated with DNA-dependent protein kinase catalytic subunit (DNA-PKcs) dependence. For this purpose, we profiled the mutational landscape across 1,319 cancer-associated genes of 67 distinct cell lines and identified numerous genes involved in homologous recombination-mediated DNA repair, including BRCA1, BRCA2, ATM, PAXIP, and RAD50, as being associated with non-oncogene addiction to DNA-PKcs. Mutations in the mismatch repair gene MSH3, which have been reported to occur recurrently in numerous human cancer entities, emerged as the most significant predictors of DNA-PKcs addiction. Concordantly, DNA-PKcs inhibition robustly induced apoptosis in MSH3-mutant cell lines in vitro and displayed remarkable single-agent efficacy against MSH3-mutant tumors in vivo. Thus, we here identify a therapeutically actionable synthetic lethal interaction between MSH3 and the non-homologous end joining kinase DNA-PKcs. Our observations recommend DNA-PKcs inhibition as a therapeutic concept for the treatment of human cancers displaying homologous recombination defects. Significance: We associate mutations in the MSH3 gene, which are frequently detected in microsatellite-instable colon cancer (~40%), with a therapeutic response to specific DNA-PKcs inhibitors. Because potent DNA-PKcs inhibitors are currently entering early clinical trials, we offer a novel opportunity to genetically stratify patients who may benefit from a DNA-PKcs-inhibitory therapy.

Original languageEnglish (US)
Pages (from-to)592-605
Number of pages14
JournalCancer Discovery
Volume4
Issue number5
DOIs
StatePublished - 2014

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DNA-Activated Protein Kinase
Genomics
Catalytic Domain
Neoplasms
Cell Line
Mutation
Genes
Recombinational DNA Repair
DNA Mismatch Repair
Neoplasm Genes
Homologous Recombination
Therapeutics
Microsatellite Repeats
Colonic Neoplasms
Phosphotransferases
Clinical Trials
Apoptosis

ASJC Scopus subject areas

  • Oncology

Cite this

Dietlein, F., Thelen, L., Jokic, M., Jachimowicz, R. D., Ivan, L., Knittel, G., ... Reinhardt, H. C. (2014). A functional cancer genomics screen identifies a druggable synthetic lethal interaction between MSH3 and PRKDC. Cancer Discovery, 4(5), 592-605. https://doi.org/10.1158/2159-8290.CD-13-0907

A functional cancer genomics screen identifies a druggable synthetic lethal interaction between MSH3 and PRKDC. / Dietlein, Felix; Thelen, Lisa; Jokic, Mladen; Jachimowicz, Ron D.; Ivan, Laura; Knittel, Gero; Leeser, Uschi; van Oers, Johanna; Edelmann, Winfried; Heukamp, Lukas C.; Reinhardt, H. Christian.

In: Cancer Discovery, Vol. 4, No. 5, 2014, p. 592-605.

Research output: Contribution to journalArticle

Dietlein, F, Thelen, L, Jokic, M, Jachimowicz, RD, Ivan, L, Knittel, G, Leeser, U, van Oers, J, Edelmann, W, Heukamp, LC & Reinhardt, HC 2014, 'A functional cancer genomics screen identifies a druggable synthetic lethal interaction between MSH3 and PRKDC', Cancer Discovery, vol. 4, no. 5, pp. 592-605. https://doi.org/10.1158/2159-8290.CD-13-0907
Dietlein, Felix ; Thelen, Lisa ; Jokic, Mladen ; Jachimowicz, Ron D. ; Ivan, Laura ; Knittel, Gero ; Leeser, Uschi ; van Oers, Johanna ; Edelmann, Winfried ; Heukamp, Lukas C. ; Reinhardt, H. Christian. / A functional cancer genomics screen identifies a druggable synthetic lethal interaction between MSH3 and PRKDC. In: Cancer Discovery. 2014 ; Vol. 4, No. 5. pp. 592-605.
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