Tumour kinome re-wiring governs resistance to palbociclib in oestrogen receptor positive breast cancers, highlighting new therapeutic modalities.
Date
2020-06-18Author
Pancholi, S
Ribas, R
Simigdala, N
Schuster, E
Nikitorowicz-Buniak, J
Ressa, A
Gao, Q
Leal, MF
Bhamra, A
Thornhill, A
Morisset, L
Montaudon, E
Sourd, L
Fitzpatrick, M
Altelaar, M
Johnston, SR
Marangoni, E
Dowsett, M
Martin, L-A
Type
Journal Article
Metadata
Show full item recordAbstract
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.
Collections
Subject
Cell Line, Tumor
Animals
Mice, Inbred BALB C
Humans
Mice, Nude
Breast Neoplasms
Tamoxifen
Piperazines
Pyridines
Retinoblastoma Protein
Receptors, Estrogen
Antineoplastic Combined Chemotherapy Protocols
Protein Kinase Inhibitors
Xenograft Model Antitumor Assays
RNA Interference
Drug Resistance, Neoplasm
Female
Cyclin-Dependent Kinase 4
Cyclin-Dependent Kinase 6
MCF-7 Cells
Fulvestrant
Research team
Endocrine Therapy Resistance
Endocrinology
Language
eng
Date accepted
2020-03-24
License start date
2020-06
Citation
Oncogene, 2020, 39 (25), pp. 4781 - 4797
Publisher
SPRINGERNATURE