The online version of this article (doi:10.1007/s00280-017-3401-y) contains supplementary material, which is available to authorized users.
Malignant pleural mesotheliomas (MPM) are most often surgically unresectable, and they respond poorly to current chemotherapy and radiation therapy. Between 23 and 64% of malignant pleural mesothelioma have somatic inactivating mutations in the BAP1 gene. BAP1 is a homologous recombination (HR) DNA repair component found in the BRCA1/BARD1 complex. Similar to BRCA1/2 deficient cancers, mutation in the BAP1 gene leads to a deficient HR pathway and increases the reliance on other DNA repair pathways. We hypothesized that BAP1-mutant MPM would require PARP1 for survival, similar to the BRCA1/2 mutant breast and ovarian cancers. Therefore, we used the clinical PARP1 inhibitors niraparib and olaparib to assess whether they could induce synthetic lethality in MPM. Surprisingly, we found that all MPM cell lines examined, regardless of BAP1 status, were addicted to PARP1-mediated DNA repair for survival. We found that niraparib and olaparib exposure markedly decreased clonal survival in multiple MPM cell lines, with and without BAP1 mutations. This clonal cell death may be due to the extensive replication fork collapse and genomic instability that PARP1 inhibition induces in MPM cells. The requirement of MPM cells for PARP1 suggests that they may generally arise from defects in HR DNA repair. More importantly, these data demonstrate that the PARP1 inhibitors could be effective in the treatment of MPM, for which little effective therapy exists.
Supplementary material 1 (PPTX 1168 kb)280_2017_3401_MOESM1_ESM.pptx
Taioli E, Wolf AS, Camacho-Rivera M et al (2015) Determinants of survival in malignant pleural mesothelioma: a surveillance, epidemiology, and end results (SEER) Study of 14,228 Patients. PLoS One. doi: 10.1371/journal.pone.0145039
Wu Y, Lee SH, Williamson EA et al (2015) EEPD1 rescues stressed replication forks and maintains genome stability by promoting end resection and homologous recombination repair. PLoS Genet 11:1–29. doi: 10.1371/journal.pgen.1005675
Mirza MR, Monk BJ, Herrstedt J et al (2016) Niraparib maintenance therapy in platinum-sensitive recurrent ovarian cancer. N Engl J Med. doi: 10.1056/NEJMoa1611310 (NEJMoa1611310)
- Synthetic lethality in malignant pleural mesothelioma with PARP1 inhibition
Gurjit Singh Sidhu
Elizabeth A. Williamson
Aruna S. Jaiswal
Thomas J. George Jr.
- Springer Berlin Heidelberg
Neu im Fachgebiet Onkologie
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