Pre-clinical evaluation of cyclin-dependent kinase 2 and 1 inhibition in anti-estrogen-sensitive and resistant breast cancer cells

Abstract

BACKGROUND: Cellular proliferation, driven by cyclin-dependent kinases (CDKs) and their cyclin partners, is deregulated in cancer. Anti-estrogens, such as tamoxifen, antagonise estrogen-induced ERa transactivation of cyclin D1, resulting in reduced CDK4/6 activity, p27 Kip1 -mediated inhibition of CDK2 and growth arrest. We hypothesised that direct inhibition of CDK2 and CDK1 may overcome the major clinical problem of anti-estrogen resistance. METHODS: The cellular effects of CDK2/1 siRNA knockdown and purine-based CDK2/1 inhibitors, NU2058 and NU6102, were measured in anti-estrogen-sensitive and resistant breast cancer cell lines. RESULTS: CDK2 knockdown caused G1 accumulation, whereas CDK1 depletion caused G2/M slowing, and dual CDK1/2 depletion resulted in further G2/M accumulation and cell death in both anti-estrogen-sensitive and resistant cells, confirming CDK2 and CDK1 as targets for breast cancer therapy. In contrast to tamoxifen, which only affected hormone-sensitive cells, NU2058 and NU6102 reduced CDK2-mediated phosphorylation of pRb, E2F transcriptional activity and proliferation, ultimately resulting in cell death, in both anti-estrogen-sensitive and resistant cells. Both drugs caused G2/M arrest, reflective of combined CDK2/1 knockdown, with a variable degree of G1 accumulation. CONCLUSION: These studies confirm the therapeutic potential of CDK2 and CDK1 inhibitors for cancer therapy, and support their use as an alternative treatment for endocrine-resistant breast cancer.

High miR-26a and low CDC2 levels associate with decreased EZH2 expression and with favorable outcome on tamoxifen in metastatic breast cancer

“…CDC2 is a mitotic cyclin-dependent Ser/Thr protein kinase and the master controller of mammalian cell–cycle regulation which is activated by CDK7 phosphorylation [31, 32]. At present, expression of CDC2 has been linked to response to tamoxifen in cell line models [33], and we now show an 8-month delay in disease progression in patients with the lowest CDC2 mRNA levels compared with those with the highest expression levels. Thus, the status of the cell cycle regulation pathway, specified by CCNE1 and CDC2 levels but also confirmed by CCNB1, CCNE2, and E2F1, seems to play a role in how the metastasis will respond to first-line tamoxifen therapy.…”

A molecular risk score based on 4 functional pathways for advanced classical Hodgkin lymphoma

“…Indeed, inhibitors of Cyclin-Cdk complexes (including Cyclin E-Cdk2, Cyclin A-Cdk2, and Cyclin B-Cdk1 complexes) are currently under preclinical and clinical investigation in different cancer types, [32][33][34] and these drugs could be considered for the treatment of advanced and refractory cHL patients. Likewise, the potential for targeting BCL2-related proteins in lymphoma is promising.…”

More power via graph-structured tests for differential expression of gene networks

“…Another small but relevant example is the sonic hedgehog receptor ptc1 regulates cell cycle pathway shown in Figure 17, which is entirely overexpressed in resistant patients, yielding a 10-fold change between the p-value with and without dimensionality reduction. The genes in this pathway are known to be related to tamoxifen resistance: CCNB1 is related to proliferation and is part of several existing tamoxifen-resistance signatures [Paik et al (2004)] and inhibition of CDC2 was already proposed as an alternative treatment for endocrine resistant tumors [Johnson et al (2010)]. 6.3.…”