Summary Lung cancer in never-smokers is an important disease often characterized by mutations in EGFR, yet risk reduction measures and effective chemopreventive strategies have not been established. We identify mTOR as a new and potentially valuable target for EGFR mutant lung cancer, as mTOR was activated in human lung cancers with EGFR mutations, which increased with acquisition of T790M mutation. In a mouse model of EGFR mutant lung cancer, activation of mTOR was an early event. As a single agent, the mTOR inhibitor rapamycin, prevented tumor development, prolonged overall survival, and improved outcomes after treatment with an irreversible EGFR TKI. These studies support clinical testing of mTOR inhibitors to prevent the development and progression of EGFR mutant lung cancers.
The insulin-like growth factor-1 (IGF-1) signaling pathway has been implicated in non-small cell lung cancer (NSCLC) outcomes and resistance to targeted therapies. However, little is known regarding the molecular mechanisms by which this pathway contributes to the biology of NSCLC. The insulin receptor substrate (IRS) proteins are cytoplasmic adaptor proteins that signal downstream of the IGF-1R and determine the functional outcomes of this signaling pathway. In this study, we assessed the expression patterns of IRS-1 and IRS-2 in NSCLC to identify associations between IRS-1 and IRS-2 expression levels and survival outcomes in the two major histological subtypes of NSCLC, adenocarcinoma (ADC) and squamous cell carcinoma (SCC). High IRS-2 expression was significantly associated with decreased overall survival in adenocarcinoma (ADC) patients, whereas low IRS-1 cytoplasmic expression showed a trend toward association with decreased overall survival in squamous cell carcinoma (SCC) patients. Tumors with low IRS-1 and high IRS-2 expression were found to be associated with poor outcomes in ADC and SCC, indicating a potential role for IRS-2 in the aggressive behavior of NSCLC. Our results suggest distinct contributions of IRS-1 and IRS-2 to the biology of ADC and SCC that impact disease progression.
◥Beclin 1 has nonautophagic functions that include its ability to regulate endocytic receptor trafficking. However, the contribution of this function to tumor suppression is poorly understood. Here, we provide in vivo evidence that Beclin 1 suppresses tumor proliferation by regulating the endocytic trafficking and degradation of the EGFR and transferrin (TFR1) receptors. Beclin 1 promoted endosomal recruitment of hepatocyte growth factor tyrosine kinase substrate (HRS), which was necessary for sorting surface receptors to intraluminal vesicles for signal silencing and lysosomal degra-dation. In tumors with low Beclin 1 expression, endosomal HRS recruitment was diminished and receptor function was sustained. Collectively, our results demonstrate a novel role for Beclin 1 in impeding tumor growth by coordinating the regulation of key growth factor and nutrient receptors. These data provide an explanation for how low levels of Beclin 1 facilitate tumor proliferation and contribute to poor cancer outcomes.Significance: Beclin 1 controls the trafficking fate of growth regulatory receptors to suppress tumor proliferation.
The insulin receptor substrate (IRS) proteins serve as essential signaling intermediates for the activation of PI3K by both the insulin-like growth factor 1 receptor (IGF-1R) and its close family member, the insulin receptor (IR). Although IRS-1 and IRS-2 share significant homology, they regulate distinct cellular responses downstream of these receptors and play divergent roles in breast cancer. To investigate the mechanism by which signaling through IRS-1 and IRS-2 results in differential outcomes, we assessed the involvement of the microtubule cytoskeleton in IRS-dependent signaling. Treatment with drugs that either stabilize or disrupt microtubules reveal that an intact microtubule cytoskeleton contributes to IRS-2-but not IRS-1-mediated activation of AKT by IGF-1. Proximal IGF-1R signaling events, including IRS tyrosine phosphorylation and recruitment of PI3K, are not inhibited by microtubule disruption, indicating that IRS-2 requires the microtubule cytoskeleton at the level of downstream effector activation. IRS-2 colocalization with tubulin is enhanced upon Taxol-mediated microtubule stabilization, which, together with the signaling data, suggests that the microtubule cytoskeleton may facilitate access of IRS-2 to downstream effectors such as AKT. Of clinical relevance is that our data reveal that expression of IRS-2 sensitizes breast carcinoma cells to apoptosis in response to treatment with microtubule-disrupting drugs, identifying IRS-2 as a potential biomarker for the response of breast cancer patients to Vinca alkaloid drug treatment.Insulin receptor substrate 1 (IRS-1) 2 and IRS-2 are cytoplasmic adaptors for the insulin receptor (IR) and insulin-like growth factor 1 receptor (IGF-1R), and they play a major role in determining the cellular response to stimulation of these receptors (1). Notably, the IRS proteins are required for the activation of PI3K downstream of the IR and IGF-1R, which activate AKT and mechanistic target of rapamycin (mTOR) to promote proliferation, survival, motility, protein synthesis, and glucose metabolism (2-5). IRS-1 and IRS-2 are expressed ubiquitously in humans, including in the normal and malignant mammary epithelium (1). Despite their considerable sequence homology, IRS-1 and IRS-2 play divergent roles in breast cancer. In vitro, studies to assess IGF-1-dependent signaling through the IRS proteins in breast carcinoma cells have revealed that IRS-1 primarily regulates proliferation and survival, whereas IRS-2 regulates motility, invasion, and glycolysis (6 -10). In vivo, overexpression of either IRS-1 or IRS-2 in the mouse mammary gland promotes mammary tumorigenesis (11). However, metastasis is diminished in the absence of Irs-2 expression and increased in the absence of Irs-1 expression (9, 12).Differential localization patterns of IRS-1 and IRS-2 in human breast tumors suggest one explanation for their divergent functions in breast cancer (13). In normal breast tissue, ductal carcinoma in situ, and invasive breast tumors, IRS-1 is primarily localized in the nucleus a...
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