Abstract B24: Triple-negative breast cancer adaptive response to MEK inhibition is regulated by the induction of super-enhancers

A predominant mechanism by which cancer cells circumvent the action of targeted kinase inhibitors is the activation of bypass signaling networks that reactivate cellular proliferation. In triple negative breast cancer (TNBC), a chief component of the adaptive response to MEK inhibition is the transcriptional upregulation and activation of receptor tyrosine kinases (RTKs), which contributes to drug resistance by reactivating ERK signaling as well as by initiating growth signaling through other kinase nodes. The cohort of RTKs activated differs between TNBC molecular subtypes and is heterogeneous even among cell lines of the same subtype; thus designing effective inhibitor combinations is challenging. Targeting the chromatin reader protein BRD4 via BET bromodomain inhibition attenuates the transcriptional adaptive response to MEK inhibition, yielding a more durable growth suppression than kinase inhibitor combinations. Yet, a detailed understanding of molecular mechanisms underlying BET bromodomain inhibitor synergy with MEK inhibitor remain unclear. We show by ChIP-seq the dynamic formation of BRD4-dense super-enhancers in response to 24 h MEK inhibition. In SUM159PT claudin-low breast cancer cells, de novo super-enhancers, whose identity were validated by histone H3 lysine 27 acetylation and MED1 co-occupancy with BRD4, were found proximal to genomic loci of DDR1, KDR, and MYLK kinases previously implicated in the adaptive MEK inhibitor response. In sum we identified 110 puta...
Source: Molecular Cancer Research - Category: Cancer & Oncology Authors: Tags: Targeted Therapies: Poster Presentations - Proffered Abstracts Source Type: research