Project 4 Abstract Triple Negative Breast Cancer (TNBC), which includes Claudin-low (CL) and Basal-like Breast Cancer (BL), exhibits frequent TP53 mutation and large-scale copy number changes. Genomic changes also result in nearly 80% of BL having MEK/ERK pathway activation, yet targeted agents have not been effective in TNBC, and chemotherapy remains the option for recurrent disease. We have shown in TNBC that targeting signaling nodes crucial for tumor growth, such as MEK/ERK, elicits rapid upregulation of alternative kinase networks contributing to escape from growth inhibition. This adaptive kinome remodeling is distinct from the time- dependent selection of pathway mutations/amplifications that constitute a well-studied resistance mechanism in multiple tumor types. Pharma is beginning to overcome some of these mutations with 2nd and 3rd generation agents, but we don?t have answers for adaptive reprogramming. Our data show that adaptive reprogramming after trametinib (MEK inhibitor) and entinostat (HDAC inhibitor) in TNBC and laptinib in HER2+ disease result in slightly different, but widespread, transcriptional upregulation of multiple kinases making combination therapy with multiple kinase inhibitors impractical and potentially toxic. The mechanism underlying the transcriptomic changes are driven epigenetically with de novo enhancer formation and dramatic genome-wide enhancer and promoter remodeling. Enhancer remodeling is not restricted to MEK inhibition; we have observed adaptive reprogramming in response to inhibitors for AKT, PI3K, HDACs (entinostat) and receptor tyrosine kinases. Importantly, using a 7-day trametinib window trial in TNBC patients we demonstrated that adaptive kinome reprogramming is recapitulated in patients. Lastly our recent data show that bromodomaim inhibitors can both prevent and reverse the epigenetic changes working as the root cause of adaptive reprogramming. Our objective is to, for the first time in patients with TNBC, establish the occurrence of rapid epigenetic reprogramming thereby developing the rationale for combination trials of clinically advancing BRD4 inhibitors with either trametinib or entinostat. This could restore targeted therapies to TNBC treatment.
Aim 1 : Determine MEKi (trametinib) and HDACi (entinostat) induced alterations in enhancer function, chromatin remodeling, and gene expression driving adaptive bypass resistance in TNBC PDXs, PDX-derived primary cells and GEM models by analyzing genomic, epigenomic and protein acetylation.
Aim 2. Use BRD4 inhibitors to determine efficacy in preventing and reversing adaptive resistance to trametinib or entinostat using Aim 1 TNBC models testing the ability of combinations to induce and maintain regression.
Aim 3. Use two window trials to obtain pretreatment and 7-day biopsies and analyze selective effects of trametinib vs entinostat on enhancer remodeling and transcriptional changes in TNBC patient tumors comparing the patient response to primary cells from the same tumor. The results would form the basis for future Phase 1/2 trials using trametinib or entinostat combinations with clinically advancing BRD4 inhibitors.

Public Health Relevance

Drug resistance remains a significant problem for successful cancer treatment. Triple Negative Breast Cancer (TNBC) lacks breast cancer-specific therapeutic targets (ER, PR, and HER2). Although the MAPK pathway is activated in at least 80% of TNBC by oncogenic signaling, targeting MEK/ERK has not resulted in therapeutic benefit, leaving chemotherapy as the bulwark of clinical treatment for resistant disease. We have demonstrated a rapid adaptive reprogramming of the genome with upregulation of numerous tyrosine kinases that results in therapeutic resistance. Our preliminary data suggest that this can be blocked at its epigenetic root using BRD4 bromodomain inhibitors. Our proposal will extend new assessments of chromatin remodeling to patients in two window trials and in primary cells derived from their tumors. The objective is to determine whether combinations of signaling inhibition agents with clinical advancing bromodomain inhibitors will be a practical therapeutic advance.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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University of North Carolina Chapel Hill
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