Genetic Alterations in the PI3K/AKT Pathway and Baseline AKT Activity Define AKT Inhibitor Sensitivity in Breast Cancer Patient-derived Xenografts.
Animals
Antineoplastic Combined Chemotherapy Protocols
/ pharmacology
Biomarkers, Tumor
/ genetics
Breast
/ pathology
Breast Neoplasms
/ genetics
Chemotherapy, Adjuvant
/ methods
Class I Phosphatidylinositol 3-Kinases
/ genetics
DNA Mutational Analysis
Drug Resistance, Neoplasm
/ genetics
Female
Humans
Mastectomy
Mice
Mutation
Paclitaxel
/ pharmacology
Prognosis
Protein Kinase Inhibitors
/ pharmacology
Proto-Oncogene Proteins c-akt
/ genetics
Pyrimidines
/ pharmacology
Pyrroles
/ pharmacology
Ribosomal Protein S6 Kinases, 70-kDa
/ metabolism
Signal Transduction
/ drug effects
TOR Serine-Threonine Kinases
/ genetics
Tuberous Sclerosis Complex 1 Protein
/ genetics
Xenograft Model Antitumor Assays
Journal
Clinical cancer research : an official journal of the American Association for Cancer Research
ISSN: 1557-3265
Titre abrégé: Clin Cancer Res
Pays: United States
ID NLM: 9502500
Informations de publication
Date de publication:
15 07 2020
15 07 2020
Historique:
received:
09
10
2019
revised:
07
02
2020
accepted:
24
03
2020
pubmed:
30
3
2020
medline:
3
11
2021
entrez:
30
3
2020
Statut:
ppublish
Résumé
AZD5363/capivasertib is a pan-AKT catalytic inhibitor with promising activity in combination with paclitaxel in triple-negative metastatic breast cancer harboring PI3K/AKT-pathway alterations and in estrogen receptor-positive breast cancer in combination with fulvestrant. Here, we aimed to identify response biomarkers and uncover mechanisms of resistance to AZD5363 and its combination with paclitaxel. Genetic and proteomic markers were analyzed in 28 HER2-negative patient-derived xenografts (PDXs) and in patient samples, and correlated to AZD5363 sensitivity as single agent and in combination with paclitaxel. Four PDX were derived from patients receiving AZD5363 in the clinic which exhibited concordant treatment response. Mutations in This study provides insight into putative predictive biomarkers of response and acquired resistance to AZD5363 in HER2-negative metastatic breast cancer.
Identifiants
pubmed: 32220884
pii: 1078-0432.CCR-19-3324
doi: 10.1158/1078-0432.CCR-19-3324
pmc: PMC7814659
mid: NIHMS1644428
doi:
Substances chimiques
Biomarkers, Tumor
0
Protein Kinase Inhibitors
0
Pyrimidines
0
Pyrroles
0
TSC1 protein, human
0
Tuberous Sclerosis Complex 1 Protein
0
MTOR protein, human
EC 2.7.1.1
Class I Phosphatidylinositol 3-Kinases
EC 2.7.1.137
PIK3CA protein, human
EC 2.7.1.137
AKT1 protein, human
EC 2.7.11.1
Proto-Oncogene Proteins c-akt
EC 2.7.11.1
Ribosomal Protein S6 Kinases, 70-kDa
EC 2.7.11.1
TOR Serine-Threonine Kinases
EC 2.7.11.1
ribosomal protein S6 kinase, 70kD, polypeptide 1
EC 2.7.11.1
Paclitaxel
P88XT4IS4D
capivasertib
WFR23M21IE
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3720-3731Subventions
Organisme : NCI NIH HHS
ID : P30 CA008748
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA016672
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA190642
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA217842
Pays : United States
Informations de copyright
©2020 American Association for Cancer Research.
Références
Cancer Cell. 2018 Sep 10;34(3):427-438.e6
pubmed: 30205045
Front Oncol. 2016 Nov 25;6:247
pubmed: 27933271
Science. 2002 May 31;296(5573):1655-7
pubmed: 12040186
J Natl Cancer Inst. 2000 Feb 2;92(3):205-16
pubmed: 10655437
Science. 2017 Mar 24;355(6331):1324-1330
pubmed: 28336670
Nat Rev Mol Cell Biol. 2009 May;10(5):307-18
pubmed: 19339977
Lancet Oncol. 2017 Oct;18(10):1360-1372
pubmed: 28800861
Front Mol Neurosci. 2015 Dec 16;8:75
pubmed: 26733799
Ann Oncol. 2019 Aug 1;30(8):1289-1297
pubmed: 31147675
Biochem J. 2013 Jun 15;452(3):499-508
pubmed: 23581296
Mol Cancer Ther. 2012 Apr;11(4):873-87
pubmed: 22294718
Proc Natl Acad Sci U S A. 1999 Mar 2;96(5):2147-52
pubmed: 10051609
Cell. 2016 Sep 22;167(1):260-274.e22
pubmed: 27641504
Cancer Cell. 2016 Aug 8;30(2):229-242
pubmed: 27451907
Cancer Discov. 2011 Jul;1(2):170-85
pubmed: 21984976
Nat Rev Clin Oncol. 2013 Mar;10(3):143-53
pubmed: 23400000
Breast Cancer Res Treat. 2012 Aug;135(1):301-6
pubmed: 22752290
Clin Cancer Res. 2020 Apr 1;26(7):1574-1585
pubmed: 31836609
Clin Cancer Res. 2018 May 1;24(9):2050-2059
pubmed: 29066505
Lancet Oncol. 2020 Mar;21(3):345-357
pubmed: 32035020
Breast Cancer Res Treat. 2012 Feb;131(3):849-58
pubmed: 21479552
Nat Med. 2015 Nov;21(11):1318-25
pubmed: 26479923
Clin Cancer Res. 2009 Dec 1;15(23):7381-8
pubmed: 19920100
Clin Cancer Res. 2013 Apr 1;19(7):1760-72
pubmed: 23287563
Annu Rev Med. 2011;62:233-47
pubmed: 20887199
J Clin Oncol. 2017 Jul 10;35(20):2251-2259
pubmed: 28489509
Nat Commun. 2018 Dec 5;9(1):5200
pubmed: 30518851
Nat Rev Clin Oncol. 2012 Apr 17;9(6):338-50
pubmed: 22508028
J Clin Oncol. 2009 Mar 10;27(8):1160-7
pubmed: 19204204
Ann Oncol. 2018 Apr 1;29(4):895-902
pubmed: 29365031
Cancer Discov. 2012 May;2(5):401-4
pubmed: 22588877
Curr Opin Genet Dev. 2010 Feb;20(1):87-90
pubmed: 20006486
Ann Oncol. 2019 May 1;30(5):774-780
pubmed: 30860570
Clin Cancer Res. 2013 Aug 15;19(16):4521-31
pubmed: 23812670
Cancer Res. 2006 Feb 1;66(3):1500-8
pubmed: 16452206
Nat Med. 2012 Jun;18(6):892-901
pubmed: 22610277
Nat Methods. 2010 Apr;7(4):248-9
pubmed: 20354512
Cell. 2007 Jun 29;129(7):1261-74
pubmed: 17604717
BMC Cancer. 2006 Dec 06;6:276
pubmed: 17150101
Clin Cancer Res. 2011 Apr 15;17(8):2591-601
pubmed: 21248301
J Biol Chem. 2007 May 11;282(19):14056-64
pubmed: 17360704
Mol Cancer Ther. 2015 Sep;14(9):2035-48
pubmed: 26116361
J Clin Invest. 2013 Jun;123(6):2551-63
pubmed: 23635776
Sci Transl Med. 2015 Apr 15;7(283):283ra51
pubmed: 25877889
Sci Signal. 2013 Apr 02;6(269):pl1
pubmed: 23550210
Mol Cancer. 2015 May 20;14:106
pubmed: 25987188
J Clin Oncol. 2020 Feb 10;38(5):423-433
pubmed: 31841354
Sci Transl Med. 2013 Jul 31;5(196):196ra99
pubmed: 23903756