Kinome Reprogramming Response To Mek Inhibition: A Window-Of-Opportunity Trial In Triple-Negative Breast Cancer (Tnbc).

512 Background: Targeted therapy (Rx) in TNBC is challenging due to heterogeneity and cancer cell kinome “reprogramming” in response to targeted kinase inhibitors (Cell 149:307, 2012). In preclinical TNBC models specific kinases (e.g., DDR1/2, PDGFRbeta, VEGFR2, AXL) are activated in response to MEK inhibition. Our studies define unique kinome reprogramming in basal-like (BBC) versus claudin-low (CL). This study compared kinome profiles of TNBC pre- and post- MEK1/2 inhibition with GSK1120212 (trametinib, T) using multiplexed inhibitor beads coupled with mass spectrometry (MIB/MS). Methods: Eligible patients (pts) with untreated TNBC received T (initial dose 1.5mg/d raised after interim analysis of kinome effects to 2mg/d) for 7 days preceding breast surgery. Fresh tumor tissue was obtained before and after T. Kinase activation state was analyzed as post:pre(-)treatment ratio; molecular subtype was by gene expression analysis. Results: Kinome response profiling was completed in 7 of 9 pts by abstract subm...