Constitutive activation of STAT3 is a common feature in many solid tumors including non-small cell lung carcinoma (NSCLC). While activation of STAT3 is commonly achieved by somatic mutations to JAK2 in hematologic malignancies, similar mutations are not often found in solid tumors. Previous work has instead suggested that STAT3 activation in solid tumors is more commonly induced by hyperactive growth factor receptors or autocrine cytokine signaling. The interplay between STAT3 activation and other well-characterized oncogenic “driver” mutations in NSCLC has not been fully characterized, though constitutive STAT3 activation has been proposed to play an important role in resistance to various small-molecule therapies that target these oncogenes. In this study we demonstrate that STAT3 is constitutively activated in human NSCLC samples and in a variety of NSCLC lines independent of activating KRAS or tyrosine kinase mutations. We further show that genetic or pharmacologic inhibition of the gp130/JAK2 signaling pathway disrupts activation of STAT3. Interestingly, treatment of NSCLC cells with the JAK1/2 inhibitor ruxolitinib has no effect on cell proliferation and viability in two-dimensional culture, but inhibits growth in soft agar and xenograft assays. These data demonstrate that JAK2/STAT3 signaling operates independent of known driver mutations in NSCLC and plays critical roles in tumor cell behavior that may not be effectively inhibited by drugs that selectively target these driver mutations.

Summary Altered cellular bioenergetics and mitochondrial function are major features of several diseases including cancer, diabetes, and neurodegenerative disorders. Given this important link to human health, we sought to define proteins within mitochondria that are critical for maintaining homeostatic ATP levels. We screened an RNAi library targeting >1,000 nuclear-encoded genes whose protein products localize to the mitochondria in multiple metabolic conditions to examine their effect on cellular ATP levels. We identified a mechanism by which electron transport chain perturbation under glycolytic conditions increased ATP production through enhanced glycolytic flux; thereby highlighting the cellular potential for metabolic plasticity. Additionally, we identified a mitochondrial adenylate kinase (AK4) that regulates cellular ATP levels, AMPK signaling, and whose expression significantly correlates with glioma patient survival. As a result, this study maps the bioenergetic landscape of >1,000 mitochondrial proteins in the context of varied metabolic substrates and begins to link key metabolic genes with clinical outcome.

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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, hepatocyte growth factor (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. Our 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 reduces downstream MET signaling to mTOR and STAT3. Loss of these critical mitogenic pathways induces cell cycle arrest and cell death due to loss of ATP production, indicating that MET and LRRK2 cooperate to promote efficient tumor cell growth and survival in these cancers.kidney cancer | kinase bioinformatics | thyroid cancer C onstitutive and unregulated activation of receptor tyrosine kinases (RTKs) is a common oncogenic mechanism in human cancers (1). Oncogenic activation of RTKs can be achieved by several different mechanisms that include somatic mutation, genetic amplification, autocrine growth factor stimulation, dysregulation of receptor trafficking pathways, or crosstalk with other kinase signaling cascades (2, 3). In many cases these separate mechanisms work in tandem to promote increased oncogenic signaling by an RTK. Prominent examples of these combinatorial mechanisms include coordinate amplification and somatic mutation of EGF receptor (EGFR) in lung cancer and coordinate overexpression of several different growth factor receptors and their cognate ligands in melanoma (4, 5).The receptor tyrosine kinase MET, located at 7q31, is frequently amplified and highly activated in human tumors (6, 7). Although activating mutations to MET have been discovered, they are found in relatively few human tumor types (8-10). Tumors that contain genomic amplification of MET may also overexpress its ligand, hepatocyte growth factor (HGF), thereby establishing an autocrine signaling loop to achieve constitutive MET activation (11-13). However, a number of tumor types demonstrate genomic amplification of MET without somatic mutation or coordinate overexpression of HGF, suggesting the existence of alternative mechanisms that activate MET in the absence of activating mutations or abundant ligand (6).In this study we sought to identify oncogenic mechanisms that promote ligand-independent MET activation by searching for kinases that are coordinately dysregulated with MET in sporadic type 1 papillary renal cell carcinoma (RCC), which is a prototypical tumor type driven by amplification and overexpression of MET (14,15). Unlike hereditary cases of papillary RCC in which MET activation is driven by specific point mutations, sporadic type 1 papillary tumors rarely demonstrate MET mutations (16, 17). Because HGF is also not significantly expressed in these tumors...