PI3K activation promotes resistance to eribulin in HER2-negative breast cancer.
Animals
Apoptosis
Biomarkers, Tumor
/ metabolism
Breast Neoplasms
/ drug therapy
Cell Cycle
Cell Proliferation
Class I Phosphatidylinositol 3-Kinases
/ genetics
Drug Resistance, Neoplasm
Female
Furans
/ pharmacology
Gene Expression Regulation, Neoplastic
Humans
Ketones
/ pharmacology
Mice
Phosphorylation
Proto-Oncogene Proteins c-akt
/ genetics
Receptor, ErbB-2
/ metabolism
Tumor Cells, Cultured
Xenograft Model Antitumor Assays
Journal
British journal of cancer
ISSN: 1532-1827
Titre abrégé: Br J Cancer
Pays: England
ID NLM: 0370635
Informations de publication
Date de publication:
04 2021
04 2021
Historique:
received:
03
07
2020
accepted:
28
01
2021
revised:
18
01
2021
pubmed:
17
3
2021
medline:
28
9
2021
entrez:
16
3
2021
Statut:
ppublish
Résumé
Eribulin is a microtubule-targeting agent approved for the treatment of advanced or metastatic breast cancer (BC) previously treated with anthracycline- and taxane-based regimens. PIK3CA mutation is associated with worse response to chemotherapy in oestrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) metastatic BC. We aimed to evaluate the role of phosphoinositide 3-kinase (PI3K)/AKT pathway mutations in eribulin resistance. Resistance to eribulin was evaluated in HER2- BC cell lines and patient-derived tumour xenografts, and correlated with a mutation in the PI3K/AKT pathway. Eleven out of 23 HER2- BC xenografts treated with eribulin exhibited disease progression. No correlation with ER status was detected. Among the resistant models, 64% carried mutations in PIK3CA, PIK3R1 or AKT1, but only 17% among the sensitive xenografts (P = 0.036). We observed that eribulin treatment induced AKT phosphorylation in vitro and in patient tumours. In agreement, the addition of PI3K inhibitors reversed primary and acquired resistance to eribulin in xenograft models, regardless of the genetic alterations in PI3K/AKT pathway or ER status. Mechanistically, PI3K blockade reduced p21 levels likely enabling apoptosis, thus sensitising to eribulin treatment. PI3K pathway activation induces primary resistance or early adaptation to eribulin, supporting the combination of PI3K inhibitors and eribulin for the treatment of HER2- BC patients.
Sections du résumé
BACKGROUND
Eribulin is a microtubule-targeting agent approved for the treatment of advanced or metastatic breast cancer (BC) previously treated with anthracycline- and taxane-based regimens. PIK3CA mutation is associated with worse response to chemotherapy in oestrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) metastatic BC. We aimed to evaluate the role of phosphoinositide 3-kinase (PI3K)/AKT pathway mutations in eribulin resistance.
METHODS
Resistance to eribulin was evaluated in HER2- BC cell lines and patient-derived tumour xenografts, and correlated with a mutation in the PI3K/AKT pathway.
RESULTS
Eleven out of 23 HER2- BC xenografts treated with eribulin exhibited disease progression. No correlation with ER status was detected. Among the resistant models, 64% carried mutations in PIK3CA, PIK3R1 or AKT1, but only 17% among the sensitive xenografts (P = 0.036). We observed that eribulin treatment induced AKT phosphorylation in vitro and in patient tumours. In agreement, the addition of PI3K inhibitors reversed primary and acquired resistance to eribulin in xenograft models, regardless of the genetic alterations in PI3K/AKT pathway or ER status. Mechanistically, PI3K blockade reduced p21 levels likely enabling apoptosis, thus sensitising to eribulin treatment.
CONCLUSIONS
PI3K pathway activation induces primary resistance or early adaptation to eribulin, supporting the combination of PI3K inhibitors and eribulin for the treatment of HER2- BC patients.
Identifiants
pubmed: 33723394
doi: 10.1038/s41416-021-01293-1
pii: 10.1038/s41416-021-01293-1
pmc: PMC8076303
doi:
Substances chimiques
Biomarkers, Tumor
0
Furans
0
Ketones
0
Class I Phosphatidylinositol 3-Kinases
EC 2.7.1.137
PIK3CA protein, human
EC 2.7.1.137
ERBB2 protein, human
EC 2.7.10.1
Receptor, ErbB-2
EC 2.7.10.1
AKT1 protein, human
EC 2.7.11.1
Proto-Oncogene Proteins c-akt
EC 2.7.11.1
eribulin
LR24G6354G
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1581-1591Subventions
Organisme : NHLBI NIH HHS
ID : T32 HL135465
Pays : United States
Références
Oncotarget. 2019 Jun 04;10(38):3667-3680
pubmed: 31217901
Cancer Res. 2005 Dec 1;65(23):10992-1000
pubmed: 16322248
Sci Transl Med. 2010 Sep 8;2(48):48ra66
pubmed: 20826841
J Clin Oncol. 2018 Apr 1;36(10):981-990
pubmed: 29470143
Proc Natl Acad Sci U S A. 2008 Sep 2;105(35):13057-62
pubmed: 18755892
Ann Oncol. 2017 Feb 1;28(2):313-320
pubmed: 27803006
Breast. 2018 Jun;39:131-138
pubmed: 29679849
Anal Biochem. 1994 May 1;218(2):314-9
pubmed: 8074286
Ann Oncol. 2019 May 1;30(5):774-780
pubmed: 30860570
Sci Transl Med. 2015 Apr 15;7(283):283ra51
pubmed: 25877889
J Formos Med Assoc. 2009 Mar;108(3):180-94
pubmed: 19293033
Mol Cell. 2008 Apr 25;30(2):203-13
pubmed: 18439899
Clin Cancer Res. 2015 Oct 1;21(19):4365-72
pubmed: 25979484
Ann Oncol. 2019 Aug 1;30(8):1289-1297
pubmed: 31147675
Breast Cancer Res Treat. 2014 Jul;146(2):321-8
pubmed: 24699910
Mol Cancer Ther. 2007 Mar;6(3):1133-42
pubmed: 17363506
Clin Cancer Res. 2011 Nov 1;17(21):6615-22
pubmed: 21859830
Ann Oncol. 2020 Mar;31(3):377-386
pubmed: 32067679
Mol Cancer Ther. 2010 Jul;9(7):1956-67
pubmed: 20571069
Cell. 2016 Sep 22;167(1):260-274.e22
pubmed: 27641504
Clin Cancer Res. 2012 Jul 15;18(14):3901-11
pubmed: 22586300
Nat Rev Clin Oncol. 2013 Mar;10(3):143-53
pubmed: 23400000
Mol Biol Cell. 2004 Sep;15(9):3965-76
pubmed: 15181148
Clin Cancer Res. 2009 Aug 15;15(16):5049-59
pubmed: 19671852
Mol Cancer Ther. 2004 Dec;3(12):1605-13
pubmed: 15634654
Mol Biol Cell. 1995 Apr;6(4):387-400
pubmed: 7626805
Nature. 2013 May 2;497(7447):108-12
pubmed: 23563269
Mol Cancer Ther. 2005 Jul;4(7):1086-95
pubmed: 16020666
Nature. 2012 Oct 4;490(7418):61-70
pubmed: 23000897
Breast Care (Basel). 2019 Apr;14(2):103-110
pubmed: 31798382
Genes Dev. 1999 Jun 15;13(12):1501-12
pubmed: 10385618
J Biol Chem. 2002 Sep 6;277(36):33490-500
pubmed: 12087097
J Med Chem. 2017 Sep 14;60(17):7524-7538
pubmed: 28829592
Nat Med. 2015 Nov;21(11):1318-25
pubmed: 26479923
Oncotarget. 2019 Aug 20;10(49):5011-5019
pubmed: 31489111
Sci Rep. 2019 Apr 8;9(1):5759
pubmed: 30962488
Cancer Res. 2000 Oct 1;60(19):5390-4
pubmed: 11034077
Cell Cycle. 2008 Apr 1;7(7):892-8
pubmed: 18414028
Nature. 2015 Feb 12;518(7538):240-4
pubmed: 25409150
J Cell Biol. 1975 Jul;66(1):188-93
pubmed: 49354
Cancer Res. 2008 Aug 1;68(15):6084-91
pubmed: 18676830
Ann Oncol. 2018 Apr 1;29(4):895-902
pubmed: 29365031
Mol Cancer Ther. 2002 Jul;1(9):707-17
pubmed: 12479367
Nat Rev Clin Oncol. 2012 Apr 17;9(6):338-50
pubmed: 22508028
Genes Dev. 1997 Feb 15;11(4):492-503
pubmed: 9042862
Curr Opin Genet Dev. 2010 Feb;20(1):87-90
pubmed: 20006486
Breast Cancer Res. 2019 Nov 8;21(1):119
pubmed: 31703728
Lancet. 2011 Mar 12;377(9769):914-23
pubmed: 21376385
Exp Cell Res. 2010 Nov 15;316(19):3197-206
pubmed: 20736003
Mol Cancer Ther. 2012 Aug;11(8):1747-57
pubmed: 22653967
Trends Cell Biol. 2003 Feb;13(2):65-70
pubmed: 12559756
Genes Dev. 1997 Apr 1;11(7):847-62
pubmed: 9106657
Int J Cancer. 2010 Mar 1;126(5):1121-31
pubmed: 19685490
Ann Oncol. 2018 Aug 1;29(8):1634-1657
pubmed: 30032243
J Natl Cancer Inst. 2000 Feb 2;92(3):205-16
pubmed: 10655437
Science. 2017 Mar 24;355(6331):1324-1330
pubmed: 28336670
Cell Death Differ. 2000 Aug;7(8):721-8
pubmed: 10918446
J Clin Oncol. 2020 Feb 10;38(5):423-433
pubmed: 31841354
ILAR J. 2006;47(1):5-14
pubmed: 16391426
Cells. 2019 Aug 30;8(9):
pubmed: 31480338
Lancet Oncol. 2017 Oct;18(10):1360-1372
pubmed: 28800861
J Mol Diagn. 2015 May;17(3):251-64
pubmed: 25801821