Targeting cell cycle and transcriptional dependencies in estrogen receptor positive breast cancer by inhibition of cyclin-dependent kinase CDK7

Breast cancer is the most common cancer worldwide, responsible for more than 600,000 deaths each year. The hormone estrogen drives breast cancer development and progression and more than 70 per cent of breast cancer patients express the estrogen receptor (ER). Endocrine therapies that inhibit ER activity are standard of care treatments for ER+ breast cancer. Unfortunately, recurrence, with endocrine therapy resistant tumours is common, with the risk of relapse remaining constant over several decades. There is, therefore, an urgent need for the development of new therapeutic approaches for therapy resistant ER+ breast cancer.

Cyclin-dependent kinase CDK7 is required for transcription of protein-coding genes and phosphorylates cell cycle CDKs to promote their association with the cognate cyclin and/or stimulation of kinase activity. As cell cycle control and transcription dependencies are common to many cancer types, we have developed selective CDK7 inhibitors, one of which is now showing promise in early stage clinic trials of advanced ER+ and triple-negative breast cancer. I will describe the biology leading up to the development of CDK7 inhibitors and our unpublished studies, including transcriptomic and proteomic profiling, large scale cancer cell line screening and genome-wide CRISPR-Cas9 knockout screens for identifying modulators of response to CDK7 inhibitors.