Shen, Xu; (2024) Understanding resistance to CDK4/6 inhibitor treatment in hormone receptor-positive metastatic breast cancer. Doctoral thesis (Ph.D), UCL (University College London).

Text Shen_10202005_thesis_revised.pdf Access restricted to UCL open access staff until 1 January 2026. Download (11MB)

Abstract

The combination of cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) with endocrine therapy is a key treatment for hormone receptor-positive (HR+) metastatic breast cancer, significantly improving progression-free survival. However, relapse during therapy is ubiquitous and limits its long-term effectiveness. While most research has focused on acquired stable resistance, this study explores early cellular responses that contribute to treatment insensitivity. Using FUCCI technology in conjunction with time-lapse microscopy, this study identifies a cell cycle-linked, non-genetic mechanism of tolerance to CDK4/6i. Cells exposed to CDK4/6i in the S, G2, M, or late G1 phases of the cell cycle are more likely to escape drug-induced G1 arrest compared to those treated in the G1 phase. This tolerance pattern has been observed in both breast cancer and non-cancerous cells, indicating a general phenomenon. Additionally, cells receiving CDK4/6i during the S/G2/M/late G1 phases exhibit a higher propensity to re-proliferate during drug holidays, periods without drug treatment, following long-term continuous CDK4/6i treatment with the clinical treatment schedule. Combination therapy of CDK4/6i palbociclib with oestrogen receptor inhibitor fulvestrant reduces tolerance in wild-type HR+ breast cancer cells but fails in ESR1-mutant cells, where CDK4/6i tolerance becomes the main driver of treatment failure. Pre-treatment with the mTOR inhibitor, everolimus or the Akt inhibitor, ipatasertib, both of which induce transient G1 arrest, significantly reduces CDK4/6i tolerance in wild-type and ESR1-mutant cells. Mechanistically, this tolerance is not due to constitutive CDK2 activation or constitutive RB1 phosphorylation but remains dependent on CDK4/6, with lysosomal entrapment of CDK4/6i emerging as a potential underlying mechanism. This study suggests that a cell cycle-linked refractory response to CDK4/6i, as opposed to genetic resistance, underlies the ubiquitously observed disease progression under therapy. Importantly, it advocates the use of agents that modulate cell cycle distribution in cancer cells towards G1 as an unexplored therapeutic strategy to prevent relapse in HR+ metastatic breast cancer patients receiving CDK4/6i treatment.

Download activity - last month

Export as CSVXMLJSON

Download activity - last 12 months

Export as JSONCSVXML

Downloads by country - last 12 months

Export as CSVXMLJSON

Archive Staff Only

View Item