Identification of novel targets for the treatment of endocrine-resistant breast cancer

Abstract

While endocrine therapy is an effective, well-tolerated treatment for oestrogen receptor positive (ER-positive) breast cancer, a large proportion of initial responders will develop hormone therapy resistance, and relapse. Two major challenges in determining the mechanisms underlying endocrine therapy resistance are our limited ability to recapitulate inter- and intra-tumour heterogeneity in vitro, and the lack of availability of tumour samples from women with disease progression or relapse, as most tissue banks are formed of diagnostic biopsies and primary tumours. The overall aim of this PhD project was to investigate mechanisms contributing to endocrine resistance, and search for common vulnerabilities that could be targeted. Examination of the transcriptome of paired patient samples from before commencement of aromatase inhibitor therapy, and following progression or relapse on therapy, confirmed the heterogeneity that is observed under the umbrella term of ER-positive breast cancer. Few common transcriptional changes were observed among the post-aromatase inhibitor therapy samples, but a trend towards upregulation of pro-proliferative signalling pathways was noted. Pre-clinical 2D and 3D models of endocrine resistance and palbociclib resistance, with different molecular backgrounds, were subjected to high-throughput drug and siRNA screens, These confirmed the importance of proliferative pathways such as PI3K-AKT-mTOR, and highlighted cyclin dependent kinase (CDK) 7 and CDK9 and their roles in cell cycle regulation and transcription as common hits in multiple cell lines. Further investigation of these targets showed that drugs targeting CDK7 and CDK9 are able to inhibit cell proliferation in endocrine-resistant and palbociclib-resistant settings, in both 2D and 3D culture. Furthermore, some of the CDK7/9 inhibitors, which are currently in clinical trials, demonstrated synergy with palbociclib treatment in both palbociclib-sensitive and palbociclib-resistant contexts. This thesis proposes that CDK7 and CDK9 are potential targets for therapy in advanced endocrine-resistant, palbociclib-resistant breast cancer settings, and that there is a potential for combination therapy of CDK7 or CDK9 inhibitors with palbociclib. Future studies are required to further elucidate the mechanism of action of these inhibitors in these resistant models, the mechanism of the synergy observed with palbociclib, and the potential for combination therapy in vivo.