Triple Negative Breast Cancer (TNBC) is an aggressive subtype of breast cancer with limited treatment options for patients. TNBCs are often driven by RAF-MEK-ERK signaling making them responsive to the FDA- approved MEK inhibitor trametinib; however patients quickly develop resistance limiting the clinical efficacy of MEK inhibition. Disruption of negative feedback loops during trametinib treatment allows tumor cells to bypass targeted inhibition through expression and activation of receptor tyrosine kinases, leading to reactivation of downstream ERK and continued tumor growth. Adaptive kinases are heterogeneous across patient samples and are dynamically activated to even bypass strategic combinations of targeted kinase inhibitors. This global resiliency of the kinome prevents durable treatment of TNBC and demonstrates that adaptive reprogramming, as a whole, needs to be blocked in order to achieve effective treatment strategies. BET bromodomain inhibitors target epigenetic histone readers to prevent adaptive expression of kinases leading to growth inhibition and cell death in vitro. This proposal will first define a mechanism by which adaptive transcription is blocked by BET bromodomain inhibitors. Secondly, this proposal will ascertain the in vivo efficacy of BET bromodomain inhibitors in combination with trametinib.
Aim 1 will establish the role of the BET bromodomain protein BRD4 in transcriptional regulation of adaptive kinases through association with the pTEFb complex using TNBC cell lines.
Aim 2 will test the in vivo efficacy of BET bromodomain treatment to block adaptive kinase expression and activation in orthotopic xenograft mouse models of TNBC. Results of the proposed aims will expand our understanding of how TNBC cells bypass MEK inhibition through adaptive transcription and will test the ability of BET bromodomain inhibitors t block adaptive resistance mechanisms leading to durable treatment of TNBC.
Breast cancer is the second leading cause of cancer-related death in women, with triple negative breast cancer (TNBC) patients having particularly poor prognosis. TNBC tumors are able to circumvent limited targeted treatment strategies with MEK inhibitors through dynamic adaptation of kinase-driven signaling pathways, making strategic combination therapies ineffective with reemergence of disease after short periods of treatment. The proposed project will continue to define mechanisms of MEK inhibitor resistance in TNBC and test the ability of novel BET bromodomain inhibitor therapies to block adaptive resistance to allow for durable treatment of TNBC.
| Zawistowski, Jon S; Bevill, Samantha M; Goulet, Daniel R et al. (2017) Enhancer Remodeling during Adaptive Bypass to MEK Inhibition Is Attenuated by Pharmacologic Targeting of the P-TEFb Complex. Cancer Discov 7:302-321 |
| Miller, Samantha M; Goulet, Daniel R; Johnson, Gary L (2017) Targeting the Breast Cancer Kinome. J Cell Physiol 232:53-60 |
