Journal
ONCOGENE
Volume 39, Issue 25, Pages 4781-4797Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41388-020-1284-6
Keywords
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Funding
- Pfizer
- NHS
- Breast Cancer Now
- Walk the Walk
- Proteins@Work - Netherlands Organisation for Scientific Research (NWO) as part of the National Roadmap Large-scale Research Facilities of the Netherlands [184.032.201]
- HighThroughput Genomics Group at the Wellcome Trust Centre for Human Genetics (Wellcome Trust) [090532/Z/09/Z]
- Arthur Foundation
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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.
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