Sensitivity of Mesothelioma Cells to PARP Inhibitors Is Not Dependent on BAP1 but Is Enhanced by Temozolomide in Cells With High-Schlafen 11 and Low-O6-methylguanine-DNA Methyltransferase Expression.
BRCA1-associated protein 1 (BAP1)
Mesothelioma
Olaparib
Poly(adenosine diphosphate-ribose) polymerase inhibitors (PARPIs)
Schlafen 11 (SLFN11)
Talazoparib
Journal
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer
ISSN: 1556-1380
Titre abrégé: J Thorac Oncol
Pays: United States
ID NLM: 101274235
Informations de publication
Date de publication:
05 2020
05 2020
Historique:
received:
13
08
2019
revised:
19
12
2019
accepted:
03
01
2020
pubmed:
1
2
2020
medline:
7
1
2021
entrez:
1
2
2020
Statut:
ppublish
Résumé
BRCA1-associated protein-1 (BAP1), a nuclear deubiquitinase thought to be involved in DNA double-strand break repair, is frequently mutated in mesothelioma. Because poly(adenosine diphosphate-ribose) polymerase inhibitors (PARPIs) induce synthetic lethality in BRCA1/2 mutant cancers, we evaluated whether BAP1 inactivating mutations confer sensitivity to PARPIs in mesothelioma and if combination therapy with temozolomide (TMZ) would be beneficial. A total of 10 patient-derived mesothelioma cell lines were generated and characterized for BAP1 mutation status, protein expression, nuclear localization, and sensitivity to the PARPIs, olaparib, and talazoparib, alone or in combination with TMZ. BAP1 deubiquitinase (DUB) activity was evaluated by ubiquitin with 7-amido-4-methylcoumarin assay. BAP1 knockout mesothelioma cell lines were generated by CRISPR-Cas9. Because Schlafen 11 (SLFN11) and O BAP1 mutations or copy-number alterations, or both were present in all 10 cell lines. Nonetheless, four cell lines exhibited intact DUB activity and two had nuclear BAP1 localization. Half maximal-inhibitory concentrations of olaparib and talazoparib ranged from 4.8 μM to greater than 50 μM and 0.039 μM to greater than 5 μM, respectively, classifying them into sensitive (two) or resistant (seven) cells, independent of their BAP1 status. Cell lines with BAP1 knockout resulted in the loss of BAP1 DUB activity but did not increase sensitivity to talazoparib. Response to PARPI tended to be associated with high SLFN11 expression, and combination with temozolomide increased sensitivity of cells with low or no MGMT expression. BAP1 status does not determine sensitivity to PARPIs in patient-derived mesothelioma cell lines. Combination of PARPI with TMZ may be beneficial for patients whose tumors have high SLFN11 and low or no MGMT expression.
Identifiants
pubmed: 32004714
pii: S1556-0864(20)30035-6
doi: 10.1016/j.jtho.2020.01.012
pmc: PMC8437153
mid: NIHMS1565565
pii:
doi:
Substances chimiques
BAP1 protein, human
0
Poly(ADP-ribose) Polymerase Inhibitors
0
Tumor Suppressor Proteins
0
Guanine
5Z93L87A1R
O-(6)-methylguanine
9B710FV2AE
O(6)-Methylguanine-DNA Methyltransferase
EC 2.1.1.63
Ubiquitin Thiolesterase
EC 3.4.19.12
Temozolomide
YF1K15M17Y
Types de publication
Journal Article
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
843-859Subventions
Organisme : Intramural NIH HHS
ID : Z01 BC006150
Pays : United States
Organisme : Intramural NIH HHS
ID : Z01 BC010816
Pays : United States
Organisme : Intramural NIH HHS
ID : ZIA BC011793
Pays : United States
Organisme : Intramural NIH HHS
ID : ZIC BC011052
Pays : United States
Commentaires et corrections
Type : CommentIn
Type : CommentIn
Informations de copyright
Published by Elsevier Inc.
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