GOLPH3 modulates mTOR signalling and rapamycin sensitivity in cancer

Abstract

Genome-wide copy number analyses of human cancers identified a frequent 5p13 amplification in several solid tumour types, including lung (56%), ovarian (38%), breast (32%), prostate (37%) and melanoma (32%). Here, using integrative analysis of a genomic profile of the region, we identify a Golgi protein, GOLPH3, as a candidate targeted for amplification. Gain- and loss-of-function studies in vitro and in vivo validated GOLPH3 as a potent oncogene. Physically, GOLPH3 localizes to the trans-Golgi network and interacts with components of the retromer complex, which in yeast has been linked to target of rapamycin (TOR) signalling. Mechanistically, GOLPH3 regulates cell size, enhances growth-factor-induced mTOR (also known as FRAP1) signalling in human cancer cells, and alters the response to an mTOR inhibitor in vivo. Thus, genomic and genetic, biological, functional and biochemical data in yeast and humans establishes GOLPH3 as a new oncogene that is commonly targeted for amplification in human cancer, and is capable of modulating the response to rapamycin, a cancer drug in clinical use. The PI3K-AKT-mTOR cascade is an important cellular signalling pathway that is active in nearly all cancers, and is therefore a prime focus of research into cancer therapeutics. A genome-wide screen has now identified a previously unknown oncogene, GOLPH3, as the target for activation by a region of amplification on chromosome 5p13 that is associated with various solid tumours. GOLPH3 protein localizes to the Golgi network and its overexpression stimulates S6 ribosomal kinase 1, which is activated by mTOR, part of the PI3K-AKT-mTOR cascade and a target for the antitumour drug rapamycin. GOLPH3 oncoprotein confers increased sensitivity to rapamycin in preclinical settings, raising the possibility that it may act as a biomarker for sensitivity to rapamycin. A genome-wide screen has identified a frequent region of amplification on chromosome 5p13 in a number of cancer types. Functional studies now identify a protein localized to the Golgi apparatus, GOLPH3, as a novel oncogene affected by this amplification which can transform cells in vitro and lead to tumour formation in vivo. GOLPH3 overexpression activates the mTOR signalling pathway and renders cancer cells sensitive to the drug rapamycin.