106447), or negative control siRNA (Ambion Inc.). cells to targeted therapies. 318:287C290; Kerbel R, Folkman J (2002) Clinical translation of angiogenesis inhibitors. 2:727C739; Kaiser J (2008) Cancer genetics: A detailed genetic portrait of the deadliest human cancers. 321:1280C1281]. Here, we report the unexpected observation that genetically diverse cancers converge at a common and obligatory growth axis instigated by HIF-2, an element of the oxygen-sensing machinery. Inhibition of HIF-2 prevents the in vivo growth and tumorigenesis of highly aggressive glioblastoma, colorectal, and nonCsmall-cell lung carcinomas and the in vitro autonomous proliferation of several others, regardless of their mutational status and tissue of origin. The concomitant deactivation of select receptor tyrosine kinases, including the EGFR and IGF1R, as well as downstream ERK/Akt signaling, suggests that HIF-2 exerts its proliferative effects by endorsing these major pathways. Consistently, silencing these receptors phenocopies the loss of HIF-2 oncogenic activity, abrogating the serum-independent growth of human cancer cells in culture. Based on these data, we propose an alternative to the predominant view that cancers exploit independent autonomous growth pathways and reveal HIF-2 as a potentially universal culprit in promoting the persistent proliferation of NSC87877 neoplastic cells. and are required for maintenance of the tumorigenic state in lung tumors and osteogenic sarcomas induced by the corresponding oncogenes Sirt7 (6, 7). The efficacy of agents targeting BCR/ABL and HER-2 in patients with chronic myeloid leukemia and breast carcinomas, respectively, similarly provides important clinical evidence that human cancers may rely wholly on a single gene, and the specific pathways it impinges on, to sustain tumor growth (8, 9). Restoration of tumor suppressor function has also been shown to inhibit cancer cell growth. A classic example of this is the reintroduction of a wild-type copy of the von Hippel-Lindau (VHL) tumor suppressor gene in clear cell renal carcinoma (RCC) (10). In this model system, loss of VHL results in the constitutive stabilization of the hypoxia-inducible factor (HIF) and its subsequent activation of the circuits that drive RCC tumorigenesis (11C14). The HIF-2 isoform in particular promotes autocrine growth signaling and cell cycle progression via epidermal growth factor receptor (EGFR) and c-Myc-dependent mechanisms (15, 16). Expression of HIF is not, of course, unique to RCC and is observed in the vast majority of overt carcinomas (17). In addition to being NSC87877 the primary cellular response to hypoxia, HIF activation is endorsed by many oncogene and tumor suppressor gene pathways that increase its synthesis or stability (18). Given that virtually all cancers exploit HIF to attain NSC87877 the angiogenic phenotype, we hypothesized that they might funnel through the HIF-2 pathway as a systemic means of acquiring growth autonomy in an analogous manner. Here, we show that silencing HIF-2 abrogates the in vivo proliferation and tumorigenesis of a panel of genetically diverse human cancers. We provide mechanistic evidence that this effect can be attributed to the activation of key receptor tyrosine kinases, including EGFR and IGF1R, and their major downstream signaling pathways. Given the catalog of genetic mutations observed in human cancers, obstructing more general processes such as angiogenesis has been favored over the specific targeting of oncogenic pathways (4, 19, 20). We propose that HIF-2 inhibition constitutes a method of targeting the autonomic growth capabilities of tumor cells and may be of broad clinical interest in the treatment of cancers with variable genetic profiles and tissue distributions. Results Inhibition of HIF-2 Prevents the Tumorigenesis of Genetically Diverse Human Cancers. The unique ability of HIF-2 to drive VHL-loss RCC growth autonomy and tumorigenesis is well-documented (11, 13, 16, 21). Since NSC87877 HIF-2 is frequently expressed in the core of human tumors we reasoned that it may also activate autonomous growth pathway(s) and contribute to the development of other cancer types. To address this prospect, we NSC87877 selected the U87MG glioblastoma, HCT116 colorectal, and A549 lung carcinoma.