Synergy between CDK9 inhibitors and palbociclib drives tumour regression in ER+ in-vivo models
While endocrine therapy and CDK4/6 inhibitors such as palbociclib have provided effective, well-tolerated treatments for estrogen receptor positive (ER-positive) breast cancer, many patients relapse with therapy-resistant disease. Determining the mechanisms underlying endocrine therapy resistance are limited by the ability to recapitulate inter- and intra-tumor heterogeneity in vitro, and the lack of availability of tumor samples from women with disease progression or relapse, as most tissue banks are formed of diagnostic biopsies and primary tumors. In this study multiple cell line models of treatment naive and resistant disease were employed for both 2D and 3D-based inhibitor screening. These screens confirmed the role of pro-proliferative pathways, such as the PI3K-AKT-mTOR pathway, in endocrine therapy resistance but additionally identified the transcription-associated cyclin-dependent kinase (CDK) 7 and CDK9 as common hits in ER+ cell lines modeling endocrine therapy-resistant disease in both the palbociclib-sensitive and palbociclib-resistant settings. CDK9 plays a key role driving the continuous production of short lived transcripts and proteins required for transcriptionally addicted cancer cell survival, however, little is known as to its role in ER+ breast cancer, particularly in the context of therapy-resistant disease. Here we demonstrate that, the CDK9 inhibitor, AZD4573, currently in clinical trials for hematological malignancies, acts synergistically with palbociclib in these ER+ in vitro 2D and 3D models and using two independent patient-derived xenograft pre-clinical models of endocrine therapy and palbociclib resistance drives tumor regression in vivo.