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Published OnlineFirst April 3, 2011; DOI: 10.1158/2159-8290.CD-ITI11-01 Cancer Discovery Publish Ahead of Print, published on April 3, 2011 as doi:10.1158/2159-8290.CD-ITI11-01 Article Name SECTION IN THIS ISSUE KRAS Rearrangements Discovered in Metastatic Prostate Cancer • ABRA identifies the first known translocation of the KRAS proto-oncogene. • The fusion protein, UBE2L3-KRAS, transformed NIH3T3 cells and altered cellular signaling. Although KRAS is a commonly activated proto-oncogene, KRAS translocations have not been previously observed. Here, Chinnaiyan and colleagues use a method termed Amplification Breakpoint Ranking and Assembly (ABRA) to identify a fusion between the KRAS and UBE2L3 genes in the avana M. Dhanasekaran , Bushra Ateeq , Atsuo T. Sasaki , metastatic prostate cancer cell John R. Prensner , Anastasia K. Yocum , Rui Wang, Daniel DU145. KRAS were also identified in a hong Cao , Yong Li , Gilbertline S. Omenn , Dorothee Pfluegerrearrangements , y Rose Kahoud , Lewis C. Cantley , Mark A. Rubin , Nallasivam subset of metastatic prostate cancers. The UBE2L3-KRAS fuy , and Arul M. Chinnaiyan sion includes most of UBE2L3 and all of KRAS, and it induced 1, 3 * 1, 3 1, 3 1, 3 1, 3 1, 3 2 9 1, 3, 6 9, 10 1, 3 9, 10 7, 8 7 • Deregulated Ras-Raf-MAPK signaling may play a role in prostate cancer metastasis. cell proliferation and focus formation when overexpressed in NIH3T3 cells. The fusion encouraged growth of tumor xenografts when these cells were implanted into nude mice. In addition, signaling was altered in these cells, with activation of AKT and p38 MAP kinase (MAPK) observed rather than the more typical activation of the MEK/ERK pathway. In prostate epithelial cells, the UBE2L3-KRAS fusion was transforming in vitro and in vivo and mislocalized to late endosomes. This work adds to a relatively short but growing list of fusion events discovered in solid tumors and suggests that deregulated RAS-RAF-MAPK signaling may play a role in metastatic prostate cancer. ≠ 1–6 ve genomics approach called amplification breakpoint ranking ysis, we nominated KRAS as a gene fusion with the ubiquitinU145 cell line, originally derived from prostate cancer metasalysis of tissues revealed that 2 of 62 metastatic prostate KRAS locus. In DU145 cells, UBE2L3-KRAS produces a fusion ch attenuates cell invasion and xenograft growth. Ectopic exprotein exhibits transforming activity in NIH 3T3 fibroblasts vitro and in vivo. In NIH 3T3 cells, UBE2L3-KRAS attenuates ged by oncogenic mutant KRAS, and instead signals via AKT inase (MAPK) pathways. This is the first report of a gene futing that this aberration may drive metastatic progression in See article, p. OF33 The BATTLE Trial: Personalizing Therapy for Lung Cancer • The BATTLE trial represents a first step toward personalized therapy for lung cancer. ption of an oncogenic gene fusion of KRAS, one of the most studment may represent the driving mutation in a rare subset of metathe importance of RAS-RAF-MAPK signaling in this disease. gy, 2National omputational and 5Urology, ncer Center, partments of nell Medical ering Cancer nter, Division ems Biology, at Cancer athology and dical Center 5-4062; Fax: INTRODUCTION To understand the characteristic features of driving gene fusions in cancer, we previously carried out a large-scale integrative analysis of cancer genomic datasets matched with gene rearrangement data (1). As part of this analysis, we observed that in many instances a small subset of tumors or cancer cell lines harboring an oncogenic gene fusion displays characteristic amplification at the site of genomic rearrangement (refs. 2–6; Supplementary Fig. S1A and B). Such amplifications usually affect a portion of the fusion gene and are generally considered secondary genetic lesions associated with disease progression, drug resistance, and poor prognosis (2, 4–8). In contrast, high-level copy number changes that result in the marked overexpression of oncogenes usually encompass the target genes at the center of overlapping amplifications across a panel of tumor samples. Thus, a “partially” amplified cancer gene may suggest that this gene participates • BATTLE is the first prospective, biopsy-mandated, biomarkerbased, adaptively randomized trial. Lung cancer is the leading cause of cancer-related deaths in the United States. Systemic chemotherapy is the standard of care for metastatic lung cancer, but targeted treatments for lung cancer, unlike those for other cancers, have been only modestly effective due to the lack of predictive biomarkers. The novel design for the phase II • The BATTLE trial integrates realtime molecular profiling for individualized treatment. Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE) trial includes prospective tumor biopsy and uses adaptive randomization, based on tumor markers analyzed in real time, to assign patients with non–small cell lung cancer to the treatment with the greatest potential benefit. Kim and colleagues report a 46% 8-week disease control rate and establish the feasibility of a new paradigm for a personalized approach to lung cancer clinical trials. ≠ See article, p. OF42 Lymphocyte and Macrophage Infiltration Predict Outcome in Breast Cancer CANCER DISCOVERY. 2011; 1(1) doi: 10.1158/2159-8274.CD-10-0022 | OF33 • Presence of CD8+ CTLs and absence of CD4+ T lymphocytes and tumor-associated macrophages (TAM) predicted better outcome. • Blockade of TAM infiltration improved sensitivity to chemotherapy and reduced tumor burden in mouse models. Recent work has shown that the immune microenvironment plays an important role in tumor biology. Here, Coussens and colleagues show that infiltration of certain types of leukocytes into breast tumor tissue predicts patient survival. In particular, OF2 | CANCER DISCOVERYAPRIL 2011 • Immunomodulatory agents may synergize with chemotherapies in treating breast cancer patients. high levels of CD8+ CTLs correlated with good outcome, whereas high levels of CD4+ T lymphocytes and TAMs correlated with poor outcome. Further, the authors found that the immune signature was predictive of relapse-free survival www.aacrjournals.org Copyright 2011 by American Association Cancer Downloaded from cancerdiscovery.aacrjournals.org on June 17, for 2017. © 2011Research. American Association for Cancer Research. Published OnlineFirst April 3, 2011; DOI: 10.1158/2159-8290.CD-ITI11-01 IN THIS ISSUE in patients whose disease had spread to their lymph nodes. Because such patients are often treated with chemotherapy, the authors hypothesized that the immune microenvironment might play a role in chemosensitivity. In a mouse model, they demonstrated that recruitment of TAMs was a common response of breast cancers to cytotoxic agents. The authors next demonstrated that treatment of tumor-bearing animals with SECTION ARTICLE RESEARCH See article, p. OF52 Laboratory Screening and Epidemiology Point to Digoxin as a Possible Therapeutic for Prostate Cancer • Digoxin is a potent inhibitor of prostate cancer cell growth A Novel Two-Stage, Transdisciplinary Study in vitro. • Digoxin users in the Health Professionals Follow-up Study had 25% lower risk of prostate cancer. Identifies Digoxin as a Possible Drug for Prostate Cancer Treatment Elizabeth A. Platz1–3,* Srinivasan Yegnasubramanian2,* Jun O. Liu2,4 Curtis R. Chong4 Joong Sup Shim4 Stacey A. Kenfield5 Meir J. Stampfer5 Walter C. Willett5 Edward Giovannucci5 William G. Nelson2–4 antibodies or a small molecule that inhibited recruitment of TAMs resulted in improved sensitivity to chemotherapy as well as reduced primary tumor burden. This result also correlated with increased levels of CD8+ CTLs and a reduction in metastasis. Finally, the authors show that CD68 and CD8 levels predict response to chemotherapy in human patients. These data provide evidence that the immune microenvironment is critical in the response to chemotherapy and suggest that immunomodulatory agents that reduce recruitment of TAMs might improve sensitivity to chemotherapy. ≠ Is it possible to repurpose already-approved therapeutics for cancer prevention or treatment? Platz and colleagues tested over 3,100 compounds, 1,811 of which are FDA approved, in a high-throughput screen to determine their effectiveness in slowing the growth of prostate cancer cell lines. Among the agents not currently used as anticancer drugs, the class of cardiac glycoside Na+/K+ ATPase inhibitors showed strong inhibition of cell growth. This class includes digoxin, a drug commonly • These data motivate future studies of digoxin as a potential therapy for prostate cancer. used to treat heart disease. The authors next examined the participants in the Health Professionals Follow-up Study, a large prospective cohort study on risk factors for chronic disease. From these data, they determined that users of digoxin had a 25% lower risk of prostate cancer than did nonusers. Although the mechanisms by which cardiac glycosides may serve as anticancer agents are not clear, this report suggests that further work is warranted. The article also provides elegant proof-of-principle that the combination of laboratorybased investigations with epidemiologic methods can be a powerful tool in translational science. ≠ See article, p. OF66 SECTION ARTICLE RESEARCH Mutations in the DDR2 Kinase Gene Identify a Novel Therapeutic Target in Squamous Cell Lung Cancer DDR2 Kinase Identified as a Therapeutic Target in Squamous Cell Carcinoma of the Lung Peter S. Hammerman1,* Martin L. Sos2,3,* Alex H. Ramos4 Chunxiao Xu1 Amit Dutt4 Wenjun Zhou5 Lear E. Brace1 Brittany A. Woods1 Wenchu Lin1 Jianming Zhang5 Xianming Deng5 Sang Min Lim5 Stefanie Heynck2 Martin Peifer2 Jeffrey R. Simard6 Michael S. Lawrence4 Robert C. Onofrio4 Helga B. Salvesen7,8 Danila Seidel2 Thomas Zander3,9 Johannes M. Heuckmann2 Alex Soltermann10 Holger Moch10 Mirjam Koker2 Frauke Leenders2 Franziska Gabler2 Silvia Querings2 Sascha Ansén9 Elisabeth Brambilla11 Christian Brambilla11 Philippe Lorimier11 Odd Terje Brustugun12 Åslaug Helland12 Iver Petersen13 Joachim H. Clement13 Harry Groen14 Wim Timens14 Hannie Sietsma14 Erich Stoelben15 Jürgen Wolf3,9 David G. Beer16 Ming Sound Tsao17 Megan Hanna1,4,18 Charles Hatton1,4,18 Michael J. Eck1 Pasi A. Janne1 Bruce E. Johnson1 Wendy Winckler4 Heidi Greulich1,4 Adam J. Bass1 Jeonghee Cho1 Daniel Rauh6,19 Nathanael S. Gray5 Kwok-Kin Wong1,21 Eric B. Haura20,* Roman K. Thomas2,3,6,* Matthew Meyerson1,4,18* • Tyrosine kinome sequencing identified DDR2 kinase mutations in lung squamous cell carcinomas (SCC). • Mutant DDR2 is transforming in vitro and in vivo, and these effects are reversed by dasatinib. Targeted therapies for lung adenocarcinoma have been clinically successful and are currently generating tremendous excitement. However, these existing therapies have little effect on lung SCCs. To identify new potential targets, Meyerson and colleagues performed sequencing of the tyrosine kinome, identifying mutations in the DDR2 kinase in 3.8% of lung SCCs and SCC cell lines. Dasatinib, an FDA-approved pharmacologic agent that inhibits multiple tyrosine kinases including DDR2, inhibited growth of • Further clinical investigation of DDR2 as a target in SCC is warranted. cell lines harboring mutant DDR2, as did knockdown of the kinase. Overexpression of mutant DDR2 in cell lines resulted in classic features of transformation. To validate these results in vivo, the authors generated a xenograft model by injecting mice with cell lines harboring DDR2 mutations. Treatment of these mice with dasatinib decreased tumor size. In a clinical trial of erlotinib plus dasatinib, one patient harboring a mutation in DDR2 but with no mutation in epidermal growth factor receptor (the target of erlotinib) displayed a response. This suggests that further investigation of DDR2 inhibition as a clinical strategy in a subset of lung squamous cell carcinoma patients is warranted. ≠ See article, p. OF76 APRIL 2011¤CANCER DISCOVERY | OF3 Downloaded from cancerdiscovery.aacrjournals.org on June 17, 2017. © 2011 American Association for Cancer Research. Published OnlineFirst April 3, 2011; DOI: 10.1158/2159-8290.CD-ITI11-01 In This Issue Cancer Discovery Published OnlineFirst April 3, 2011. Updated version Supplementary Material E-mail alerts Reprints and Subscriptions Permissions Access the most recent version of this article at: doi:10.1158/2159-8290.CD-ITI11-01 Access the most recent supplemental material at: http://cancerdiscovery.aacrjournals.org/content/suppl/2011/03/31/2159-8290.CD-ITI11-01v1. 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