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In cancer, genetically activated proto-oncogenes often induce 'upstream' dependency on the activity of the mutant oncoprotein. Therapeutic inhibition of these activated oncoproteins can induce massive apoptosis of tumor cells, leading to sometimes dramatic tumor regressions in patients. The PI3K and MAPK signaling pathways are central regulators of oncogenic transformation and tumor maintenance. We hypothesized that upstream dependency engages either one of these pathways preferentially to induce 'downstream' dependency. Therefore, we analyzed whether downstream pathway dependency segregates by genetic aberrations upstream in lung cancer cell lines. Here, we show by systematically linking drug response to genomic aberrations in non-small-cell lung cancer, as well as in cell lines of other tumor types and in a series of in vivo cancer models, that tumors with genetically activated receptor tyrosine kinases depend on PI3K signaling, whereas tumors with mutations in the RAS/RAF axis depend on MAPK signaling. However, efficacy of downstream pathway inhibition was limited by release of negative feedback loops on the reciprocal pathway. By contrast, combined blockade of both pathways was able to overcome the reciprocal pathway activation induced by inhibitor-mediated release of negative feedback loops and resulted in a significant increase in apoptosis and tumor shrinkage. Thus, by using a systematic chemo-genomics approach, we identify genetic lesions connected to PI3K and MAPK pathway activation and provide a rationale for combined inhibition of both pathways. Our findings may have implications for patient stratification in clinical trials. cancer genomics | combination therapy | high-throughput cell line screening | oncogene dependency doi/10.1073/pnas.0907325106

Lung cancer is the leading cause of cancer-related mortality not only in the United States but also around the world. In North America, lung cancer has become more predominant among former than current smokers. Yet in some countries, such as China, which has experienced a dramatic increase in the cigarette smoking rate during the past 2 decades, a peak in lung cancer incidence is still expected. Approximately two-thirds of adult Chinese men are smokers, representing one-third of all smokers worldwide. Non-small cell lung cancer accounts for 85% of all lung cancer cases in the United States. After the initial diagnosis, accurate staging of non-small cell lung cancer using computed tomography or positron emission tomography is crucial for determining appropriate therapy. When feasible, surgical resection remains the single most consistent and successful option for cure. However, close to 70% of patients with lung cancer present with locally advanced or metastatic disease at the time of diagnosis. Chemotherapy is beneficial for patients with metastatic disease, and the administration of concurrent chemotherapy and radiation is indicated for stage III lung cancer. The introduction of angiogenesis, epidermal growth factor receptor inhibitors, and other new anticancer agents is changing the present and future of this disease and will certainly increase the number of lung cancer survivors. We identified studies for this review by searching the MEDLINE and PubMed databases for English-language articles published from January 1, 1980, through January 31, 2008. Key terms used for this search included non-small cell lung cancer, adenocarcinoma, squamous cell carcinoma, bronchioalveolar cell carcinoma, large cell carcinoma, lung cancer epidemiology, genetics, survivorship, surgery, radiation therapy, chemotherapy, targeted therapy, bevacizumab, erlotinib, and epidermal growth factor receptor. Mayo Clin Proc. 2008;83(5):584-594, Lung cancer has become the number one killer among cancers worldwide. Although lung cancer remains the leading cause of cancer-related mortality in the United States, its incidence is decreasing. In [...]