Abstract 4036: Chromosomal amplification of LRRK2 is required for oncogenic MET signaling in papillary renal and thyroid carcinomas

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL The receptor tyrosine kinase MET is frequently amplified in human tumors, resulting in high cell surface densities and constitutive activation even in the absence of growth factor stimulation by its endogenous ligand, HGF. We sought to identify mechanisms of signaling crosstalk that promote MET activation by searching for kinases that are coordinately dysregulated with wild-type MET in human tumors. Bioinformatic analysis identified leucine-rich repeat kinase-2 (LRRK2), which is amplified and overexpressed in papillary renal and thyroid carcinomas. Downregulation of LRRK2 in cultured tumor cells compromises MET activation and selectively impairs MET signaling to mTOR and STAT3. Loss of these critical mitogenic pathways induces cell cycle arrest and cell death concomitant with loss of ATP production and induction of autophagy. Interestingly, knockdown of LRRK2 precisely phenocopies treatment of tumor cells with the endocytic inhibitor chlorpromazine, suggesting that LRRK2 is required for efficient internalization or post-endocytic trafficking of activated MET receptors. We propose that coordinate amplification of LRRK2 and MET functions to promote endosomal signal transduction by MET, which is required for transformation in papillary renal and thyroid cancers. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4036. doi:10.1158/1538-7445.AM2011-4036