Gene expression profiling of homologous recombination repair pathway indicates susceptibility for olaparib treatment in malignant pleural mesothelioma in vitro.
Acid Anhydride Hydrolases
Antineoplastic Agents
/ pharmacology
Apoptosis
/ drug effects
Aurora Kinase A
/ genetics
Biomarkers, Tumor
/ genetics
Cell Line, Tumor
Cisplatin
/ pharmacology
DNA Repair Enzymes
/ genetics
DNA-Binding Proteins
/ genetics
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
/ drug effects
Homologous Recombination
/ genetics
Humans
Lung Neoplasms
/ genetics
Mesothelioma
/ genetics
Mesothelioma, Malignant
Pemetrexed
/ pharmacology
Phthalazines
/ pharmacology
Piperazines
/ pharmacology
Poly(ADP-ribose) Polymerase Inhibitors
/ pharmacology
Recombinational DNA Repair
/ genetics
BRCAness - BAP1
Malignant pleural mesothelioma - overall survival
Olaparib
PARP1
Journal
BMC cancer
ISSN: 1471-2407
Titre abrégé: BMC Cancer
Pays: England
ID NLM: 100967800
Informations de publication
Date de publication:
30 Jan 2019
30 Jan 2019
Historique:
received:
02
07
2018
accepted:
22
01
2019
entrez:
1
2
2019
pubmed:
1
2
2019
medline:
6
5
2019
Statut:
epublish
Résumé
Malignant pleural mesothelioma (MPM) is a tumour arising from pleural cavities with poor prognosis. Multimodality treatment with pemetrexed combined with cisplatin shows unsatisfying response-rates of 40%. The reasons for the rather poor efficacy of chemotherapeutic treatment are largely unknown. However, it is conceivable that DNA repair mechanisms lead to an impaired therapy response. We hypothesize a major role of homologous recombination (HR) for genome stability and survival of this tumour. Therefore, we analysed genes compiled under the term "BRCAness". An inhibition of this pathway with olaparib might abrogate this effect and induce apoptosis. We investigated the response of three MPM cell lines and lung fibroblasts serving as a control to treatment with pemetrexed, cisplatin and olaparib. Furthermore, we aimed to find possible correlations between response and gene expression patterns associated with BRCAness phenotype. Therefore, 91 clinical MPM samples were digitally screened for gene expression patterns of HR members. A BRCAness-dependent increase of apoptosis and senescence during olaparib-based treatment of BRCA-associated-protein 1 (BAP1)-mutated cell lines was observed. The gene expression pattern identified could be found in approx. 10% of patient samples. Against this background, patients could be grouped according to their defects in the HR system. Gene expression levels of Aurora Kinase A (AURKA), RAD50 as well as DNA damage-binding protein 2 (DDB2) could be identified as prognostic markers in MPM. Defects in HR compiled under the term BRCAness are a common event in MPM. The present data can lead to a better understanding of the underlaying cellular mechanisms and leave the door wide open for new therapeutic approaches for this severe disease with infaust prognosis. Response to Poly (ADP-ribose)-Polymerase (PARP)-Inhibition could be demonstrated in the BAP1-mutated NCI-H2452 cells, especially when combined with cisplatin. Thus, this combination therapy might be effective for up to 2/3 of patients, promising to enhance patients' clinical management and outcome.
Sections du résumé
BACKGROUND
BACKGROUND
Malignant pleural mesothelioma (MPM) is a tumour arising from pleural cavities with poor prognosis. Multimodality treatment with pemetrexed combined with cisplatin shows unsatisfying response-rates of 40%. The reasons for the rather poor efficacy of chemotherapeutic treatment are largely unknown. However, it is conceivable that DNA repair mechanisms lead to an impaired therapy response. We hypothesize a major role of homologous recombination (HR) for genome stability and survival of this tumour. Therefore, we analysed genes compiled under the term "BRCAness". An inhibition of this pathway with olaparib might abrogate this effect and induce apoptosis.
METHODS
METHODS
We investigated the response of three MPM cell lines and lung fibroblasts serving as a control to treatment with pemetrexed, cisplatin and olaparib. Furthermore, we aimed to find possible correlations between response and gene expression patterns associated with BRCAness phenotype. Therefore, 91 clinical MPM samples were digitally screened for gene expression patterns of HR members.
RESULTS
RESULTS
A BRCAness-dependent increase of apoptosis and senescence during olaparib-based treatment of BRCA-associated-protein 1 (BAP1)-mutated cell lines was observed. The gene expression pattern identified could be found in approx. 10% of patient samples. Against this background, patients could be grouped according to their defects in the HR system. Gene expression levels of Aurora Kinase A (AURKA), RAD50 as well as DNA damage-binding protein 2 (DDB2) could be identified as prognostic markers in MPM.
CONCLUSIONS
CONCLUSIONS
Defects in HR compiled under the term BRCAness are a common event in MPM. The present data can lead to a better understanding of the underlaying cellular mechanisms and leave the door wide open for new therapeutic approaches for this severe disease with infaust prognosis. Response to Poly (ADP-ribose)-Polymerase (PARP)-Inhibition could be demonstrated in the BAP1-mutated NCI-H2452 cells, especially when combined with cisplatin. Thus, this combination therapy might be effective for up to 2/3 of patients, promising to enhance patients' clinical management and outcome.
Identifiants
pubmed: 30700254
doi: 10.1186/s12885-019-5314-0
pii: 10.1186/s12885-019-5314-0
pmc: PMC6354412
doi:
Substances chimiques
Antineoplastic Agents
0
Biomarkers, Tumor
0
DDB2 protein, human
0
DNA-Binding Proteins
0
Phthalazines
0
Piperazines
0
Poly(ADP-ribose) Polymerase Inhibitors
0
Pemetrexed
04Q9AIZ7NO
AURKA protein, human
EC 2.7.11.1
Aurora Kinase A
EC 2.7.11.1
Acid Anhydride Hydrolases
EC 3.6.-
RAD50 protein, human
EC 3.6.-
DNA Repair Enzymes
EC 6.5.1.-
Cisplatin
Q20Q21Q62J
olaparib
WOH1JD9AR8
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
108Références
Mol Cell. 2001 Feb;7(2):263-72
pubmed: 11239455
Proc Natl Acad Sci U S A. 2001 Jul 17;98(15):8644-9
pubmed: 11447276
EMBO J. 2001 Sep 3;20(17):4704-16
pubmed: 11532935
Oncogene. 2001 Sep 27;20(43):6245-9
pubmed: 11593434
Nat Rev Cancer. 2003 Jan;3(1):23-34
pubmed: 12509764
Ann Oncol. 2004 Feb;15(2):257-60
pubmed: 14760119
Nat Rev Cancer. 2004 Oct;4(10):814-9
pubmed: 15510162
DNA Repair (Amst). 2007 Jul 1;6(7):885-90
pubmed: 17481966
Eur J Cardiothorac Surg. 2008 Feb;33(2):307-13
pubmed: 18164622
Int J Cancer. 2009 Jan 1;124(1):201-7
pubmed: 18792097
J Med Chem. 2008 Oct 23;51(20):6581-91
pubmed: 18800822
Proc Natl Acad Sci U S A. 2008 Nov 4;105(44):17079-84
pubmed: 18971340
Lung Cancer. 2010 Jan;67(1):57-68
pubmed: 19380173
N Engl J Med. 2009 Jul 9;361(2):123-34
pubmed: 19553641
Int J Cancer. 2010 Aug 15;127(4):977-88
pubmed: 20013802
Am J Respir Cell Mol Biol. 2011 Nov;45(5):906-14
pubmed: 21454801
Nat Genet. 2011 Jun 05;43(7):668-72
pubmed: 21642991
Nat Genet. 2011 Aug 28;43(10):1022-5
pubmed: 21874000
Nature. 2012 Jan 18;481(7381):287-94
pubmed: 22258607
J Thorac Oncol. 2012 Sep;7(9):1440-8
pubmed: 22895141
Prostate Cancer Prostatic Dis. 2013 Sep;16(3):233-8
pubmed: 23670255
Anticancer Res. 2013 Sep;33(9):3553-61
pubmed: 24023280
Curr Opin Oncol. 2014 Mar;26(2):171-81
pubmed: 24441503
Nat Rev Cancer. 2016 Feb;16(2):110-20
pubmed: 26775620
J Thorac Oncol. 2016 Feb;11(2):142-54
pubmed: 26811225
Gynecol Oncol. 2016 Apr;141(1):57-64
pubmed: 27016230
Pol J Pathol. 2016 Jun;67(2):108-13
pubmed: 27543864
J Cancer. 2016 Sep 13;7(13):1915-1925
pubmed: 27698933
J Thorac Oncol. 2017 Aug;12(8):1309-1319
pubmed: 28389374
Virchows Arch. 2017 Jun;470(6):627-637
pubmed: 28466156
Epidemiol Prev. 2017 Jan-Feb;41(2):140-143
pubmed: 28627156
Cancer Lett. 2017 Oct 1;405:38-45
pubmed: 28687356
Ann Transl Med. 2017 Jun;5(11):238
pubmed: 28706906
Ann Transl Med. 2017 Jun;5(11):239
pubmed: 28706907
Transl Lung Cancer Res. 2017 Jun;6(3):248-258
pubmed: 28713670
Cancer Chemother Pharmacol. 2017 Oct;80(4):861-867
pubmed: 28756516
Oncotarget. 2018 Apr 27;9(32):22254-22268
pubmed: 29854276