Inactive VEGFR2(R1032Q) exerts pro‐oncogenic activity through heterodimerization with wild‐type receptor

Abstract

The vascular endothelial growth factor receptor 2 is commonly dysregulated in cancer, resulting in aberrant intracellular signaling, altered metabolism, increased cell proliferation and poor prognosis. VEGFR2 dysregulation mainly results from an increase in its abundance and/or activity following gene amplifications, aberrant autocrine/paracrine activation or point mutations. However, little is known about the effects of VEGFR2 mutations on tumor progression and response to VEGFR2‐targeted TKi. Here we investigated the mechanism by which the most frequent non‐synonymous inactivating mutation R1032Q of VEGFR2 promotes tumor growth. Our analysis showed that mutated VEGFR2R1032Q forms functional heterodimers with wild‐type receptor in the absence of ligands. The co‐expression of VEGFR2R1032Q with VEGFR2WT alters the dynamics of VEGFR2, increasing receptor mobile fraction on cell membrane. The VEGFR2WT/VEGFR2R1032Q heterocomplex is hyperphosphorylated and increases the VEGFR2‐associated intracellular signaling in the absence of exogenous VEGF stimulation. In a model of melanoma heterozygous for the R1032Q mutation of VEGFR2, the heterodimeric complex VEGFR2WT/VEGFR2R1032Q triggers pro‐oncogenic events altering cell metabolism, increasing cell growth and metastasis. Remarkably, in this melanoma model the VEGFR2‐targeted inhibitor Linifanib is devoid of anti‐proliferative effects. Overall our data reveal a ligand‐independent inter‐receptor kinase activation of VEGFR2/VEGFR2R1032Q heterodimers which drive tumor progression and hamper drug response. This novel mechanism of activation of VEGFR2 in cancer may be exploited to develop novel therapeutic approaches to treat tumors harboring inactivating heterozygous mutations of VEGFR2.