Therapeutic targeting of dual CDK4/6 inhibitor and endocrine resistant breast cancer

Approximately 75% of all breast cancers express estrogen receptor (ER), and receive adjuvant endocrine therapy, but ~35% of these patients recur with endocrine therapy resistant disease. Once metastatic, endocrine resistant breast cancer is incurable and contributes to >50% of breast cancer deaths [1]. The recent introduction of CDK4/6 inhibitors offers these patients a next line of therapy. Combination therapy of CDK4/6 inhibitors with endocrine therapy has doubled the progression free survival of patients with advanced ER-positive breast cancer in seminal phase 3 studies, and is now FDA approved for use in the first line setting [2-5]. It is expected that most ER-positive breast cancer patients in countries with CDK4/6 inhibitors therapy approval will receive endocrine therapy and CDK4/6 inhibitors during the course of their treatment.

In our proposal, we use endocrine therapy and CDK4/6 inhibitor resistance models, in vitro and in vivo, to discover new therapeutic targets by identifying the mechanisms of resistance. We aim to validate which of these mechanisms are unique to single agent and/or combination therapy by comparing both the mono- and dual-therapy resistance models, and expand the comparison across publicly cohorts, including Turner et al. (2019) (GEO accession GSE128500) [2], on endocrine therapy and CDK4/6 inhibitor trial. We will subsequently perform pre-clinical screening of new therapeutic regimes to identify tailored treatments for dual resistant advanced ER-positive breast cancer. This will lead to major impact on the practice of personalised medicine, with trials that rapidly accelerate the progress of breast cancer management and advance sourcing support for further innovative clinical interventions in Australia and worldwide.