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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
5P50CA058223-26
Application #
10011768
Study Section
Special Emphasis Panel (ZCA1)
Project Start
1997-08-05
Project End
2023-08-31
Budget Start
2020-09-01
Budget End
2021-08-31
Support Year
26
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Type
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Sharma, Priyanka; López-Tarruella, Sara; García-Saenz, José Angel et al. (2018) Pathological Response and Survival in Triple-Negative Breast Cancer Following Neoadjuvant Carboplatin plus Docetaxel. Clin Cancer Res 24:5820-5829
Siegel, Marni B; He, Xiaping; Hoadley, Katherine A et al. (2018) Integrated RNA and DNA sequencing reveals early drivers of metastatic breast cancer. J Clin Invest 128:1371-1383
Kumar, Sunil; Lindsay, Daniel; Chen, Q Brent et al. (2018) Tracking plasma DNA mutation dynamics in estrogen receptor positive metastatic breast cancer with dPCR-SEQ. NPJ Breast Cancer 4:39
Smith, Christof C; Beckermann, Kathryn E; Bortone, Dante S et al. (2018) Endogenous retroviral signatures predict immunotherapy response in clear cell renal cell carcinoma. J Clin Invest 128:4804-4820
Wheeler, Stephanie B; Spencer, Jennifer C; Pinheiro, Laura C et al. (2018) Financial Impact of Breast Cancer in Black Versus White Women. J Clin Oncol 36:1695-1701
Hong, Chi-Chen; Sucheston-Campbell, Lara E; Liu, Song et al. (2018) Genetic Variants in Immune-Related Pathways and Breast Cancer Risk in African American Women in the AMBER Consortium. Cancer Epidemiol Biomarkers Prev 27:321-330
Tanioka, Maki; Mott, Kevin R; Hollern, Daniel P et al. (2018) Identification of Jun loss promotes resistance to histone deacetylase inhibitor entinostat through Myc signaling in luminal breast cancer. Genome Med 10:86
Tanioka, Maki; Fan, Cheng; Parker, Joel S et al. (2018) Integrated Analysis of RNA and DNA from the Phase III Trial CALGB 40601 Identifies Predictors of Response to Trastuzumab-Based Neoadjuvant Chemotherapy in HER2-Positive Breast Cancer. Clin Cancer Res 24:5292-5304
Mundt, Filip; Rajput, Sandeep; Li, Shunqiang et al. (2018) Mass Spectrometry-Based Proteomics Reveals Potential Roles of NEK9 and MAP2K4 in Resistance to PI3K Inhibition in Triple-Negative Breast Cancers. Cancer Res 78:2732-2746
Takaku, Motoki; Grimm, Sara A; Roberts, John D et al. (2018) GATA3 zinc finger 2 mutations reprogram the breast cancer transcriptional network. Nat Commun 9:1059

Showing the most recent 10 out of 598 publications