Introduction: Estrogen receptor positive (ER+) is the most common type of breast cancer and despite the development of ER targeted (endocrine) therapies, 30-50% of ER+ patients treated with endocrine therapy will develop resistant, aggressive disease. Along with endocrine therapy, CDK4/6 inhibitors are now the standard of care for treatment of advanced ER+ breast cancer. The initial success of CDK4/6 inhibitors in increasing progression free survival, is hampered by the rapid acquisition of drug resistance, with 30% of patients presenting with recurring disease within 2 years. Although effective in delaying tumour growth and progression, resistance to CDK4/6 inhibitors emerges rapidly. Mechanisms of CDK4/6 inhibitor resistance have been well studied in recent years and have exposed many pivotal mechanisms of resistance which enhance proliferation. However the role of the pro-senescence response to CDK4/6 inhibition and how it changes in drug resistance is not yet fully characterised. Previous studies have highlighted senescence as a therapeutically significant response to CDK4/6 inhibitor therapy ((Fitsiou, Soto-Gamez, & Demaria, 2021; Galiana et al., 2020; Wagner & Gil, 2020). Uncovering senescence-associated factors and mechanisms in ER+ disease and CDK4/6 inhibitor resistance is crucial to our understanding of resistance, and may allow the development of new therapeutic avenues.
Objective: We aim to identify pivotal genes and pathways of senescence which modulate resistance to endocrine therapies and CDK4/6 inhibitors in ER+ breast cancer and investigate therapeutic strategies to enhance positive effects of senescence.
Methods: CRISPR-Cas9 screen using the Brunello library will be used across ER+ breast cancer models to identify senescence genes and pathways that prevent cells becoming senescent post therapy. Analysing how these senescence-associated genes and pathways correlate with disease progression and patient outcome will determine whether these genes and pathways could be potential therapeutic targets. Across a variety of ER+ models, including models of ER+ therapy resistance and patient derived xenografts, we will apply genetic and epigenetic compounds targeting identified senescence-associated factors to enhance the senescence response in ER+ breast cancer.
Conclusions: Uncovering senescence-associated factors in ER+ breast cancer could allow us to develop novel therapeutic strategies for ER+ breast cancer through the reactivation of senescence pathways.