Morphoproteomics of VEGF pathway mediators as evidence of reversible resistance to VEGF-TKIs demonstrated by expression of activated ERK and STAT3 in metastatic renal cell carcinoma (mRCC).

Abstract

e15552 Background: Resistance to vascular endothelial growth factors (VEGF)-tyrosine kinase inhibitors (TKIs) (e.g., sunitinib, sorafenib) may be a result of changes in the tumor microenvironment and to the selection of resistant clones and permanent genetic changes. This has been demonstrated in mouse xenograft models where there was tumor shrinkage following reintroduction of sorafenib after a 1 week break (Zhang 2011 PLoS One). Methods: We applied morphoproteomic analysis to biopsy specimens of mRCC after a treatment break with VEGF-TKIs. Constitutive activation evidenced by expression (≤3) of p-extracellular signal-regulated kinase (ERK) 1/2 and p-signal transducer and activator of transcription (STAT) 3 in the nuclear compartments (≤3) indicates signaling through the VEGF pathway. Results: Strong overexpression of p-ERK1/2 and p-STAT3 with VEGF tyrosine kinase inhibitors indicates reactivation of the VEGF pathways (Table). Conclusions: Morphoproteomics confirms constitutive activation of the prosurvival ERK and STAT3 pathways after a treatment break indicating reversibility in resistance patterns to therapy with VEGF-TKIs indicating that the drugs can be reintroduced after having progressed on the same therapy. [Table: see text]