Global Survey of Phosphotyrosine Signaling Identifies Oncogenic Kinases in Lung Cancer

Cell Signaling Technology, 3 Trask Lane, Danvers, MA 01923, USA.
Cell (Impact Factor: 32.24). 01/2008; 131(6):1190-203. DOI: 10.1016/j.cell.2007.11.025
Source: PubMed


Despite the success of tyrosine kinase-based cancer therapeutics, for most solid tumors the tyrosine kinases that drive disease remain unknown, limiting our ability to identify drug targets and predict response. Here we present the first large-scale survey of tyrosine kinase activity in lung cancer. Using a phosphoproteomic approach, we characterize tyrosine kinase signaling across 41 non-small cell lung cancer (NSCLC) cell lines and over 150 NSCLC tumors. Profiles of phosphotyrosine signaling are generated and analyzed to identify known oncogenic kinases such as EGFR and c-Met as well as novel ALK and ROS fusion proteins. Other activated tyrosine kinases such as PDGFRalpha and DDR1 not previously implicated in the genesis of NSCLC are also identified. By focusing on activated cell circuitry, the approach outlined here provides insight into cancer biology not available at the chromosomal and transcriptional levels and can be applied broadly across all human cancers.

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Available from: Michael J Comb,
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    • "Rearrangements of the gene encoding the receptor tyrosine kinase anaplastic lymphoma kinase (ALK) in non-small cell lung cancer (NSCLC) were identified in 2007 and shown to contribute to carcinogenesis in a subgroup of lung cancer patients [1] [2] [3]. While only 3–5% of NSCLC tumors are ALK-rearrangement-positive [1] [2] [4], this translates into a considerable number of patients affected worldwide. Crizotinib (XALKORI; Pfizer Inc., New York, NY, USA) is an inhibitor of ALK, MET, and ROS1 [5] [6] [7]. "
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    ABSTRACT: Within 4 years of the discovery of anaplastic lymphoma kinase (ALK) rearrangements in non-small cell lung cancer (NSCLC), the ALK inhibitor crizotinib gained US and European approval for the treatment of advanced ALK-positive NSCLC. This was due to the striking response data observed with crizotinib in phase I and II trials in patients with ALK-positive NSCLC, as well as the favorable tolerability and safety profile observed. Recently published phase III data established crizotinib as the new standard of care in the second-line setting for this NSCLC molecular subset. A consequence of such rapid approval, however, is the limited clinical experience and relative paucity of information concerning optimal therapy management. In this review, we discuss the development of crizotinib and the clinical relevance of its safety profile, examining crizotinib-associated adverse events in detail and making specific management recommendations. Crizotinib-associated adverse events were mostly mild to moderate in severity in clinical studies, and appropriate monitoring and supportive therapies are considered effective in avoiding the need for dose interruption or reduction in most cases. Therapy management of patients following disease progression on crizotinib is also discussed. Based on available clinical data, it is evident that patients may have prolonged benefit from crizotinib after Response Evaluation Criteria in Solid Tumors-defined disease progression, and crizotinib should be continued for as long as the patient derives benefit.
    Lung Cancer 12/2014; 87(2). DOI:10.1016/j.lungcan.2014.12.010 · 3.96 Impact Factor
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    • "This assay is less expensive than FISH, but the sensitivity is related to the antibody clone and to the protein expression levels. Furthermore, RT- PCR is frequently combined with FISH and IHC for the detection of rearrangements; although it is highly sensitive and cheaper, the main limitation of RT-PCR is the poor quality of RNA obtained from FFPE tissues (Charest et al., 2003b; Rikova et al., 2007; Gu et al., 2011). "
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    ABSTRACT: ROS1 rearrangements have been detected in a variety of tumors and are considered as suitable targets of anticancer therapies. We developed a new, quick, specific, and sensitive PCR test to screen for the FIG-ROS1 fusion and applied it to a series of Italian patients with bile duct carcinoma (BTC). Formalin-fixed, paraffin-embedded tissues, derived from 65 Italian BTC patients, and six cell lines were analyzed by nested PCR to investigate the prevalence of a previously reported FIG-ROS1 fusion. The specificity and sensitivity of nested PCR were investigated in FIG-ROS1 positive U118MG cells in reconstitution experiments with peripheral blood mononuclear cells. We found that six out of 65 (9%) BTC patients were positive for the FIG-ROS1 fusion, comprising two out of 14 (14%) gallbladder carcinoma (GBC) patients and four out of 25 (16%) extrahepatic cholangiocarcinoma (ECC) patients. None of the 26 intrahepatic cholangiocarcinoma cases harbored the FIG-ROS1 fusion. All the cell lines were negative for this variant. In conclusion, 14–16% of GBC and ECC were positive for FIG-ROS1. This may have clinical implications, since these patients will potentially benefit from the treatment with specific ROS1 inhibitors. © 2014 Wiley Periodicals, Inc.
    Genes Chromosomes and Cancer 12/2014; 53(12). DOI:10.1002/gcc.22212 · 4.04 Impact Factor
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    • "In recent years, the identification of genetic abnormalities that may underlie oncogenic development and progression have revolutionized oncology research [7]. A translocation in the gene encoding the receptor tyrosine kinase anaplastic lymphoma kinase (ALK), leading to the expression of ALK fusion proteins, was first reported in NSCLC patients in 2007 [8, 9]. The activated ALK fusion proteins result in aberrant ALK signaling and oncogenic transformation through several molecular signaling pathways, including PI3K/AKT/mTOR, JAK/STAT, and RAS/MEK/ERK [10]. "
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    ABSTRACT: Background Crizotinib was granted accelerated approval by the Food and Drug Administration in 2011 for the treatment of anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC). To evaluate the efficacy and safety of crizotinib, we performed a meta-analysis of published clinical trials using the random effect model. Methods The efficacy and safety of crizotinib was evaluated based on 1-year overall survival (OS), progression-free survival (PFS), overall response rate (ORR), partial response, complete response, stable disease, and dose reduction or cessation because of crizotinib toxicity. Results Six clinical trials were included in the meta-analysis. Crizotinib treatment demonstrated a 1-year OS of 66.8% (95% CI, 52.2–78.8%) and a PFS of 8.6 months (95% CI, 7.3–9.9 months). The aggregate ORR, partial response and complete response rates were 61.2%, 59.8% and 1.5%, respectively. The proportion of patients achieving stable disease was 42.6% (95% CI, 17.3–72.5%). The most frequently reported adverse effects of crizotinib were mild visual disturbances, nausea, vomiting, diarrhea, constipation, edema, reduction in glomerular filtration rate, and generally reversible but sometimes severe elevations in aspartate aminotransferase and alanine aminotransferase. The proportion of patients who required dose reduction or cessation because of crizotinib toxicity was 6.5% (95% CI, 4.1–10.1%). Conclusions This meta-analysis revealed extended survival and improved response rates in patients treated with crizotinib. As a novel, targeted anticancer agent, crizotinib appears to be a favorable treatment option for patients with locally advanced or metastatic ALK-positive NSCLC.
    BMC Cancer 09/2014; 14(1):683. DOI:10.1186/1471-2407-14-683 · 3.36 Impact Factor
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