Abstract B25: BET bromodomain inhibition targets adaptive responses to lapatinib in HER2-positive breast cancer

Small molecule kinase inhibitors that target oncogene-driven cancers often elicit dramatic initial clinical responses, but adaptive responses from the kinome and transcriptome limit their efficacy and generate resistance. Such adaptive bypass responses are driven by the disruption of regulatory feedback and feedforward loops that govern many signaling networks. To understand these responses in the context of HER2-addicted cancer, we used a chemical proteomics method to assay whole-kinome activation dynamics in cells treated with the small molecule HER2/EGFR tyrosine kinase inhibitor lapatinib. We observed a rapid reactivation of oncogenic signaling and a global re-wiring of kinase signaling networks including activation of receptor tyrosine kinases (RTKs) HER3, DDR1, FGFRs, IGF1R, INSR, and multiple Ephrin receptors, as well as intracellular nodes PKC, SRC family kinases and FAK. Targeting compensatory kinases with a series of kinase inhibitors provided variable and incremental enhancement of growth inhibition but could not prevent resistant colony formation. Cell line heterogeneity and functional redundancy among compensatory kinases added further difficulty to effectively predict the best combination therapy.This presents a dilemma where combinations of two or even three kinase inhibitors would be insufficient to suppress all the bypass tracks that were rapidly induced by HER2 inhibition. RNAseq revealed a 2-fold dysregulation of approximately 20% of expressed genes within ...
Source: Molecular Cancer Research - Category: Cancer & Oncology Authors: Tags: Targeted Therapies: Poster Presentations - Proffered Abstracts Source Type: research