Tumour kinome re-wiring governs resistance to palbociclib in oestrogen receptor positive breast cancers, highlighting new therapeutic modalities.
Animals
Antineoplastic Combined Chemotherapy Protocols
/ pharmacology
Breast Neoplasms
/ genetics
Cell Line, Tumor
Cyclin-Dependent Kinase 4
/ genetics
Cyclin-Dependent Kinase 6
/ genetics
Drug Resistance, Neoplasm
/ drug effects
Female
Fulvestrant
/ administration & dosage
Humans
MCF-7 Cells
Mice, Inbred BALB C
Mice, Nude
Piperazines
/ pharmacology
Protein Kinase Inhibitors
/ pharmacology
Pyridines
/ pharmacology
RNA Interference
Receptors, Estrogen
/ genetics
Retinoblastoma Protein
/ genetics
Tamoxifen
/ administration & dosage
Xenograft Model Antitumor Assays
/ methods
Journal
Oncogene
ISSN: 1476-5594
Titre abrégé: Oncogene
Pays: England
ID NLM: 8711562
Informations de publication
Date de publication:
06 2020
06 2020
Historique:
received:
24
05
2019
accepted:
24
03
2020
revised:
18
03
2020
pubmed:
21
4
2020
medline:
15
12
2020
entrez:
21
4
2020
Statut:
ppublish
Résumé
Combination of CDK4/6 inhibitors and endocrine therapy improves clinical outcome in advanced oestrogen receptor (ER)-positive breast cancer, however relapse is inevitable. Here, we show in model systems that other than loss of RB1 few gene-copy number (CN) alterations are associated with irreversible-resistance to endocrine therapy and subsequent secondary resistance to palbociclib. Resistance to palbociclib occurred as a result of tumour cell re-wiring leading to increased expression of EGFR, MAPK, CDK4, CDK2, CDK7, CCNE1 and CCNE2. Resistance altered the ER genome wide-binding pattern, leading to decreased expression of 'classical' oestrogen-regulated genes and was accompanied by reduced sensitivity to fulvestrant and tamoxifen. Persistent CDK4 blockade decreased phosphorylation of tuberous sclerosis complex 2 (TSC2) enhancing EGFR signalling, leading to the re-wiring of ER. Kinome-knockdown confirmed dependency on ERBB-signalling and G2/M-checkpoint proteins such as WEE1, together with the cell cycle master regulator, CDK7. Noteworthy, sensitivity to CDK7 inhibition was associated with loss of ER and RB1 CN. Overall, we show that resistance to CDK4/6 inhibitors is dependent on kinase re-wiring and the redeployment of signalling cascades previously associated with endocrine resistance and highlights new therapeutic networks that can be exploited upon relapse after CDK4/6 inhibition.
Identifiants
pubmed: 32307447
doi: 10.1038/s41388-020-1284-6
pii: 10.1038/s41388-020-1284-6
pmc: PMC7299844
doi:
Substances chimiques
Piperazines
0
Protein Kinase Inhibitors
0
Pyridines
0
Receptors, Estrogen
0
Retinoblastoma Protein
0
Tamoxifen
094ZI81Y45
Fulvestrant
22X328QOC4
Cyclin-Dependent Kinase 4
EC 2.7.11.22
Cyclin-Dependent Kinase 6
EC 2.7.11.22
palbociclib
G9ZF61LE7G
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
4781-4797Subventions
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 090532/Z/09/Z
Pays : United Kingdom
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