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Cancer Discovery Research Article Activating HER2 Mutations in HER2 Gene Amplification Negative Breast Cancer Ron Bose, Shyam M. Kavuri, Adam C. Searleman, Wei Shen, Dong Shen, Daniel C. Koboldt, John Monsey, Nicholas Goel, Adam B. Aronson, Shunqiang Li, Cynthia X. Ma, Li Ding, Elaine R. Mardis, and Matthew J. Ellis Ron Bose Matthew J. Ellis Abstract Data from 8 breast cancer genome-sequencing projects identified 25 patients with HER2 somatic mutations in cancers lacking HER2 gene amplification. To determine the phenotype of these mutations, we functionally characterized 13 HER2 mutations using in vitro kinase assays, protein structure analysis, cell culture, and xenograft experiments. Seven of these mutations are activating mutations, including G309A, D769H, D769Y, V777L, P780ins, V842I, and R896C. HER2 in-frame deletion 755–759, which is homologous to EGF receptor (EGFR) exon 19 in-frame deletions, had a neomorphic phenotype with increased phosphorylation of EGFR or HER3. L755S produced lapatinib resistance, but was not an activating mutation in our experimental systems. All of these mutations were sensitive to the irreversible kinase inhibitor, neratinib. These findings show that HER2 somatic mutation is an alternative mechanism to activate HER2 in breast cancer and they validate HER2 somatic mutations as drug targets for breast cancer treatment. Significance: We show that the majority of HER2 somatic mutations in breast cancer patients are activating mutations that likely drive tumorigenesis. Several patients had mutations that are resistant to the reversible HER2 inhibitor lapatinib, but are sensitive to the irreversible HER2 inhibitor, neratinib. Our results suggest that patients with HER2 mutation–positive breast cancers could benefit from existing HER2-targeted drugs. Cancer Discov; 3(2); 224–37. ©2013 AACR. Cancer Discov February 2013 3:224–37; Published OnlineFirst December 7, 2012; doi:10.1158/2159-8290.CD-12-0349 Research Article First-in-Humans Trial of an RNA Interference Therapeutic Targeting VEGF and KSP in Cancer Patients with Liver Involvement Josep Tabernero, Geoffrey I. Shapiro, Patricia M. LoRusso, Andres Cervantes, Gary K. Schwartz, Glen J. Weiss, Luis Paz-Ares, Daniel C. Cho, Jeffrey R. Infante, Maria Alsina, Mrinal M. Gounder, Rick Falzone, Jamie Harrop, Amy C. Seila White, Iva Toudjarska, David Bumcrot, Rachel E. Meyers, Gregory Hinkle, Nenad Svrzikapa, Renta M. Hutabarat, Valerie A. Clausen, Jeffrey Cehelsky, Saraswathy V. Nochur, Christina Gamba-Vitalo, Akshay K. Vaishnaw, Dinah W.Y. Sah, Jared A. Gollob, and Howard A. Burris III Josep Tabernero Abstract RNA interference (RNAi) is a potent and specific mechanism for regulating gene expression. Harnessing RNAi to silence genes involved in disease holds promise for the development of a new class of therapeutics. Delivery is key to realizing the potential of RNAi, and lipid nanoparticles (LNP) have proved effective in delivery of siRNAs to the liver and to tumors in animals. To examine the activity and safety of LNP-formulated siRNAs in humans, we initiated a trial of ALN-VSP, an LNP formulation of siRNAs targeting VEGF and kinesin spindle protein (KSP), in patients with cancer. Here, we show detection of drug in tumor biopsies, siRNA-mediated mRNA cleavage in the liver, pharmacodynamics suggestive of target downregulation, and antitumor activity, including complete regression of liver metastases in endometrial cancer. In addition, we show that biweekly intravenous administration of ALN-VSP was safe and well tolerated. These data provide proof-of-concept for RNAi therapeutics in humans and form the basis for further development in cancer. Significance: The findings in this report show safety, pharmacokinetics, RNAi mechanism of action, and clinical activity with a novel first-in-class LNP-formulated RNAi therapeutic in patients with cancer. The ability to harness RNAi to facilitate specific multitargeting, as well as increase the number of druggable targets, has important implications for future drug development in oncology. Cancer Discov; 3(4); 406–17. ©2012 AACR. Cancer Discov April 2013 3:406–17; Published OnlineFirst January 28, 2013; doi:10.1158/2159-8290.CD-12-0429 2 aacrjournals.org
Cancer Discovery Research Article Amplification of the MET Receptor Drives Resistance to Anti-EGFR Therapies in Colorectal Cancer Alberto Bardelli, Simona Corso, Andrea Bertotti, Sebastijan Hobor, Emanuele Valtorta, Giulia Siravegna, Andrea Sartore-Bianchi, Elisa Scala, Andrea Cassingena, Davide Zecchin, Maria Apicella, Giorgia Migliardi, Francesco Galimi, Calogero Lauricella, Carlo Zanon, Timothy Perera, Silvio Veronese, Giorgio Corti, Alessio Amatu, Marcello Gambacorta, Luis A. Diaz Jr, Mark Sausen, Victor E. Velculescu, Paolo Comoglio, Livio Trusolino, Federica Di Nicolantonio, Silvia Giordano, and Salvatore Siena Alberto Bardelli Silvia Giordano Abstract EGF receptor (EGFR)-targeted monoclonal antibodies are effective in a subset of metastatic colorectal cancers. Inevitably, all patients develop resistance, which occurs through emergence of KRAS mutations in approximately 50% of the cases. We show that amplification of the MET proto-oncogene is associated with acquired resistance in tumors that do not develop KRAS mutations during anti-EGFR therapy. Amplification of the MET locus was present in circulating tumor DNA before relapse was clinically evident. Functional studies show that MET activation confers resistance to anti-EGFR therapy both in vitro and in vivo. Notably, in patient-derived colorectal cancer xenografts, MET amplification correlated with resistance to EGFR blockade, which could be overcome by MET kinase inhibitors. These results highlight the role of MET in mediating primary and secondary resistance to anti-EGFR therapies in colorectal cancer and encourage the use of MET inhibitors in patients displaying resistance as a result of MET amplification. Significance: Amplification of the MET proto-oncogene is responsible for de novo and acquired resistance to anti-EGFR therapy in a subset of colorectal cancers. As multiple anti- MET therapeutic strategies are available, these findings offer immediate novel opportunities to design clinical studies. Cancer Discov; 3(6); 658–73. ©2013 AACR. Cancer Discov June 2013 3:658–73; Published OnlineFirst June 6, 2013; doi:10.1158/2159-8290.CD-12-0558 Research Brief Identification of Targetable FGFR Gene Fusions in Diverse Cancers Yi-Mi Wu, Fengyun Su, Shanker Kalyana-Sundaram, Nickolay Khazanov, Bushra Ateeq, Xuhong Cao, Robert J. Lonigro, Pankaj Vats, Rui Wang, Su-Fang Lin, Ann-Joy Cheng, Lakshmi P. Kunju, Javed Siddiqui, Scott A. Tomlins, Peter Wyngaard, Seth Sadis, Sameek Roychowdhury, Maha H. Hussain, Felix Y. Feng, Mark M. Zalupski, Moshe Talpaz, Kenneth J. Pienta, Daniel R. Rhodes, Dan R. Robinson, and Arul M. Chinnaiyan Dan R. Robinson Arul M. Chinnaiyan Abstract Through a prospective clinical sequencing program for advanced cancers, four index cases were identified which harbor gene rearrangements of FGFR2, including patients with cholangiocarcinoma, breast cancer, and prostate cancer. After extending our assessment of FGFR rearrangements across multiple tumor cohorts, we identified additional FGFR fusions with intact kinase domains in lung squamous cell cancer, bladder cancer, thyroid cancer, oral cancer, glioblastoma, and head and neck squamous cell cancer. All FGFR fusion partners tested exhibit oligomerization capability, suggesting a shared mode of kinase activation. Overexpression of FGFR fusion proteins induced cell proliferation. Two bladder cancer cell lines that harbor FGFR3 fusion proteins exhibited enhanced susceptibility to pharmacologic inhibition in vitro and in vivo. Because of the combinatorial possibilities of FGFR family fusion to a variety of oligomerization partners, clinical sequencing efforts, which incorporate transcriptome analysis for gene fusions, are poised to identify rare, targetable FGFR fusions across diverse cancer types. Significance: High-throughput sequencing technologies facilitate defining the mutational landscape of human cancers, which will lead to more precise treatment of patients with cancer. Here, through integrative sequencing efforts, we identified a variety of FGFR gene fusions in a spectrum of human cancers. FGFR fusions are active kinases. Cells harboring FGFR fusions showed enhanced sensitivity to the FGFR inhibitors PD173074 and pazopanib, suggesting that patients with cancer with FGFR fusions may benefit from targeted FGFR kinase inhibition. Cancer Discov; 3(6); 636–47. ©2013 AACR. Cancer Discov June 2013 3:636–47; Published OnlineFirst April 4, 2013; doi:10.1158/2159-8290.CD-13-0050 The Best of the AACR Journals 3
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