Vulnerability to low-dose combination of irinotecan and niraparib in ATM-mutated colorectal cancer.
Chemopotentiation
Colorectal cancer
Combination treatment
DNA damage response
Homologous recombination
Irinotecan
PARP inhibitors
Synergism
Journal
Journal of experimental & clinical cancer research : CR
ISSN: 1756-9966
Titre abrégé: J Exp Clin Cancer Res
Pays: England
ID NLM: 8308647
Informations de publication
Date de publication:
06 Jan 2021
06 Jan 2021
Historique:
received:
12
09
2020
accepted:
11
12
2020
entrez:
7
1
2021
pubmed:
8
1
2021
medline:
31
8
2021
Statut:
epublish
Résumé
Despite the advancements in new therapies for colorectal cancer (CRC), chemotherapy still constitutes the mainstay of the medical treatment. For this reason, new strategies to increase the efficacy of chemotherapy are desirable. Poly-ADP-Ribose Polymerase inhibitors (PARPi) have shown to increase the activity of DNA damaging chemotherapeutics used in the treatment of CRC, however previous clinical trials failed to validate these results and pointed out dose-limiting toxicities that hamper the use of such combinations in unselected CRC patients. Nevertheless, in these studies little attention was paid to the mutational status of homologous recombination repair (HRR) genes. We tested the combination of the PARPi niraparib with either 5-fluorouracil, oxaliplatin or irinotecan (SN38) in a panel of 12 molecularly annotated CRC cell lines, encompassing the 4 consensus molecular subtypes (CMSs). Synergism was calculated using the Chou-Talalay method for drug interaction. A correlation between synergism and genetic alterations in genes involved in homologous recombination (HR) repair was performed. We used clonogenic assays, mice xenograft models and patient-derived 3D spheroids to validate the results. The induction of DNA damage was studied by immunofluorescence. We showed that human CRC cell lines, as well as patient-derived 3D spheroids, harboring pathogenic ATM mutations are significantly vulnerable to PARPi/chemotherapy combination at low doses, regardless of consensus molecular subtypes (CMS) and microsatellite status. The strongest synergism was shown for the combination of niraparib with irinotecan, and the presence of ATM mutations was associated to a delay in the resolution of double strand breaks (DSBs) through HRR and DNA damage persistence. This work demonstrates that a numerically relevant subset of CRCs carrying heterozygous ATM mutations may benefit from the combination treatment with low doses of niraparib and irinotecan, suggesting a new potential approach in the treatment of ATM-mutated CRC, that deserves to be prospectively validated in clinical trials.
Sections du résumé
BACKGROUND
BACKGROUND
Despite the advancements in new therapies for colorectal cancer (CRC), chemotherapy still constitutes the mainstay of the medical treatment. For this reason, new strategies to increase the efficacy of chemotherapy are desirable. Poly-ADP-Ribose Polymerase inhibitors (PARPi) have shown to increase the activity of DNA damaging chemotherapeutics used in the treatment of CRC, however previous clinical trials failed to validate these results and pointed out dose-limiting toxicities that hamper the use of such combinations in unselected CRC patients. Nevertheless, in these studies little attention was paid to the mutational status of homologous recombination repair (HRR) genes.
METHODS
METHODS
We tested the combination of the PARPi niraparib with either 5-fluorouracil, oxaliplatin or irinotecan (SN38) in a panel of 12 molecularly annotated CRC cell lines, encompassing the 4 consensus molecular subtypes (CMSs). Synergism was calculated using the Chou-Talalay method for drug interaction. A correlation between synergism and genetic alterations in genes involved in homologous recombination (HR) repair was performed. We used clonogenic assays, mice xenograft models and patient-derived 3D spheroids to validate the results. The induction of DNA damage was studied by immunofluorescence.
RESULTS
RESULTS
We showed that human CRC cell lines, as well as patient-derived 3D spheroids, harboring pathogenic ATM mutations are significantly vulnerable to PARPi/chemotherapy combination at low doses, regardless of consensus molecular subtypes (CMS) and microsatellite status. The strongest synergism was shown for the combination of niraparib with irinotecan, and the presence of ATM mutations was associated to a delay in the resolution of double strand breaks (DSBs) through HRR and DNA damage persistence.
CONCLUSIONS
CONCLUSIONS
This work demonstrates that a numerically relevant subset of CRCs carrying heterozygous ATM mutations may benefit from the combination treatment with low doses of niraparib and irinotecan, suggesting a new potential approach in the treatment of ATM-mutated CRC, that deserves to be prospectively validated in clinical trials.
Identifiants
pubmed: 33407715
doi: 10.1186/s13046-020-01811-8
pii: 10.1186/s13046-020-01811-8
pmc: PMC7789007
doi:
Substances chimiques
Indazoles
0
Piperidines
0
Irinotecan
7673326042
niraparib
HMC2H89N35
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
15Subventions
Organisme : Associazione Italiana per la Ricerca sul Cancro
ID : MFAG-2015-ID:7778
Organisme : Associazione Italiana per la Ricerca sul Cancro
ID : IG-2013-ID:14800
Organisme : Regione Campania
ID : I-CURE
Références
Nature. 2019 May;569(7757):503-508
pubmed: 31068700
Nucleic Acids Res. 2019 Jan 8;47(D1):D941-D947
pubmed: 30371878
Hum Mutat. 2011 May;32(5):557-63
pubmed: 21520333
J Clin Oncol. 1993 Nov;11(11):2194-204
pubmed: 8229134
Nat Commun. 2018 Aug 17;9(1):3292
pubmed: 30120226
J Exp Clin Cancer Res. 2016 Nov 24;35(1):179
pubmed: 27884198
Clin Cancer Res. 2017 Jul 15;23(14):3489-3498
pubmed: 28364015
Cancer Res. 2010 Jan 15;70(2):440-6
pubmed: 20068163
Ann Oncol. 2016 Aug;27(8):1386-422
pubmed: 27380959
Nat Genet. 2019 May;51(5):912-919
pubmed: 30988514
Nature. 2012 Mar 28;483(7391):603-7
pubmed: 22460905
Clin Cancer Res. 2020 Mar 15;26(6):1372-1384
pubmed: 31831554
Science. 2017 Mar 17;355(6330):1152-1158
pubmed: 28302823
Nucleic Acids Res. 2015 Jan;43(Database issue):D805-11
pubmed: 25355519
Mol Cancer Ther. 2016 Aug;15(8):1781-91
pubmed: 27413114
Cancers (Basel). 2020 Mar 14;12(3):
pubmed: 32183301
Cancer Treat Rev. 2019 Feb;73:1-9
pubmed: 30543930
Cancer Res. 2011 Apr 1;71(7):2632-42
pubmed: 21300766
Nat Rev Cancer. 2012 Dec;12(12):801-17
pubmed: 23175119
Clin Pharmacokinet. 1997 Oct;33(4):245-59
pubmed: 9342501
Invest New Drugs. 2013 Apr;31(2):461-8
pubmed: 23054213
Sci Rep. 2019 Feb 27;9(1):2858
pubmed: 30814645
Crit Rev Oncol Hematol. 2016 Dec;108:73-85
pubmed: 27931843
Mol Oncol. 2019 Apr;13(4):681-700
pubmed: 30714316
Cancer Discov. 2012 May;2(5):401-4
pubmed: 22588877
J Med Chem. 2015 Apr 23;58(8):3302-14
pubmed: 25761096
Oncogene. 2014 Jun 26;33(26):3351-60
pubmed: 23851492
Cancer Cell Int. 2015 Feb 04;15(1):14
pubmed: 25685067
Invest New Drugs. 2016 Aug;34(4):450-7
pubmed: 27075016
Cancer Res. 1990 Mar 15;50(6):1715-20
pubmed: 2306725
Transl Oncol. 2017 Apr;10(2):190-196
pubmed: 28182994
Sci Signal. 2013 Apr 02;6(269):pl1
pubmed: 23550210
Mol Cancer Ther. 2014 May;13(5):1170-80
pubmed: 24577941
Bioinformatics. 2015 May 15;31(10):1536-43
pubmed: 25583119
Clin Cancer Res. 2018 Feb 15;24(4):794-806
pubmed: 29242316
CA Cancer J Clin. 2018 Nov;68(6):394-424
pubmed: 30207593
Oncologist. 2016 Feb;21(2):172-7
pubmed: 26786262
Nat Commun. 2017 Oct 11;8(1):857
pubmed: 29021619
Ann Oncol. 2020 Dec;31(12):1606-1622
pubmed: 33004253
Cancer Cell. 2018 Jan 8;33(1):125-136.e3
pubmed: 29316426
Clin Cancer Res. 2001 Aug;7(8):2182-94
pubmed: 11489791