CANCER DISCOVERY CONTENTSSay What? The Activity of the Polyamine Biosynthesis Inhibitor Difl...
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iv | CANCER DISCOVERYSEPTEMBER 2013 www.aacrjournals.org CANCER DISCOVERY CONTENTS SEPTEMBER 2013 ≠ VOLUME 3 ≠ NUMBER 9 Cell-Autonomous and Non–Cell-Autonomous Mechanisms of HGF/MET–Driven Resistance to Targeted Therapies: From Basic Research to a Clinical Perspective . . . . . . . . . . . . . . . . . . . . .978 S. Corso and S. Giordano Dominant Role of Oncogene Dosage and Absence of Tumor Suppressor Activity in Nras-Driven Hematopoietic Transformation . . . . . . . . . . . . . . . . .993 J. Xu, K.M. Haigis, A.J. Firestone, M.E. McNerney, Q. Li, E. Davis, S.-C. Chen, J. Nakitandwe, J. Downing, T. Jacks, M.M. Le Beau, and K. Shannon Précis: Increased expression of mutant Nras, not loss of wild-type Nras, drives transformation in the hematopoietic lineage. Mechanism-Based Epigenetic Chemosensitization Therapy of Diffuse Large B-Cell Lymphoma . . . . . . . . . . . . . . . . . . . 1002 T. Clozel, S.N. Yang, R.L. Elstrom, W. Tam, P. Martin, M. Kormaksson, S. Banerjee, A. Vasanthakumar, B. Culjkovic, D.W. Scott, S. Wyman, M. Leser, R. Shaknovich, A. Chadburn, F. Tabbo, L.A. Godley, R.D. Gascoyne, K.L. Borden, G. Inghirami, J.P. Leonard, A. Melnick, and L. Cerchietti Précis: Treatment with DNA methyltrans- ferase inhibitors overcomes chemoresist- ance in high-risk DLBCL via demethylation and reactivation of SMAD1. See commentary, p. 968 A Clinically Relevant Androgen Receptor Mutation Confers Resistance to Second-Generation Antiandrogens Enzalutamide and ARN-509 . . . . . . . . . . . . . . . . 1020 J.D. Joseph, N. Lu, J. Qian, J. Sensintaffar, G. Shao, D. Brigham, M. Moon, E.C. Maneval, I. Chen, B. Darimont, and J.H. Hager Précis: An AR F876L mutation confers ligand-specific resistance and is found in the circulating tumor DNA of ARN- 509–treated patients with progressive castration-resistant prostate cancer. See commentary, p. 971 REVIEW RESEARCH BRIEF RESEARCH ARTICLES Highlighted research articles . . . . . . . . . . . . . . . . . . . . . . . . . 953 Important news stories affecting the community. . . . . . . . . . . . . . . . . . . . . 958 Q&A: Crystal Mackall, John Maris on Pediatrics. . . . . . . 961 Stopping Breast Cancer Before It Starts . . . . . . . . . . . . . . . . . 962 Selected highlights of recent articles of exceptional significance from the cancer literature . . . . . . . . . . . . . 963 For more News and Research Watch, visit Cancer Discovery online at http://CDnews.aacrjournals.org. In The Spotlight Epigenetic Approaches for Chemosensitization of Refractory Diffuse Large B-Cell Lymphomas . . . . . . . . . . . . .968 J.J. Steinhardt and R.B. Gartenhaus See article, p. 1002 Resistance Emerges to Second- Generation Antiandrogens in Prostate Cancer . . . . . . . . . . . . . . .971 W.G. Nelson and S. Yegnasubramanian See article, p. 1020 See article, p. 1030 Say What? The Activity of the Polyamine Biosynthesis Inhibitor Difluoromethylornithine in Chemoprevention Is a Result of Reduced Thymidine Pools? . . . .975 R.A. Casero Jr See article, p. 1072 IN THIS ISSUE NEWS IN BRIEF NEWS IN DEPTH RESEARCH WATCH ONLINE VIEWS Research. on February 13, 2020. © 2013 American Association for Cancer cancerdiscovery.aacrjournals.org Downloaded from
Transcript of CANCER DISCOVERY CONTENTSSay What? The Activity of the Polyamine Biosynthesis Inhibitor Difl...
iv | CANCER DISCOVERY�SEPTEMBER 2013 www.aacrjournals.org
CANCERDISCOVERY CONTENTSSEPTEMBER 2013 ≠ VOLUME 3 ≠ NUMBER 9
Cell-Autonomous and Non–Cell-Autonomous Mechanisms of HGF/MET–Driven Resistance to Targeted Therapies: From Basic Research to a Clinical Perspective . . . . . . . . . . . . . . . . . . . . .978S. Corso and S. Giordano
Dominant Role of Oncogene Dosage and Absence of Tumor Suppressor Activity in Nras-Driven Hematopoietic Transformation . . . . . . . . . . . . . . . . .993J. Xu, K.M. Haigis, A.J. Firestone, M.E. McNerney, Q. Li, E. Davis, S.-C. Chen, J. Nakitandwe, J. Downing, T. Jacks, M.M. Le Beau, and K. ShannonPrécis: Increased expression of mutant Nras, not loss of wild-type Nras, drives transformation in the hematopoietic lineage.
Mechanism-Based Epigenetic Chemosensitization Therapy of Diffuse Large B-Cell Lymphoma . . . . . . . . . . . . . . . . . . . 1002T. Clozel, S.N. Yang, R.L. Elstrom, W. Tam, P. Martin, M. Kormaksson, S. Banerjee, A. Vasanthakumar, B. Culjkovic, D.W. Scott, S. Wyman, M. Leser, R. Shaknovich, A. Chadburn, F. Tabbo, L.A. Godley, R.D. Gascoyne, K.L. Borden, G. Inghirami, J.P. Leonard, A. Melnick, and L. CerchiettiPrécis: Treatment with DNA methyltrans-ferase inhibitors overcomes chemoresist-ance in high-risk DLBCL via demethylation and reactivation of SMAD1.
See commentary, p. 968
A Clinically Relevant Androgen Receptor Mutation Confers Resistance to Second-Generation Antiandrogens Enzalutamide and ARN-509 . . . . . . . . . . . . . . . . 1020J.D. Joseph, N. Lu, J. Qian, J. Sensintaffar, G. Shao, D. Brigham, M. Moon, E.C. Maneval, I. Chen, B. Darimont, and J.H. Hager Précis: An ARF876L mutation confers ligand-specifi c resistance and is found in the circulating tumor DNA of ARN-509–treated patients with progressive castration-resistant prostate cancer.
See commentary, p. 971
REVIEW
RESEARCHBRIEF
RESEARCHARTICLES
Highlighted research articles . . . . . . . . . . . . . . . . . . . . . . . . . 953
Important news stories affecting the community . . . . . . . . . . . . . . . . . . . . . 958
Q&A: Crystal Mackall, John Maris on Pediatrics . . . . . . . 961
Stopping Breast Cancer Before It Starts . . . . . . . . . . . . . . . . . 962
Selected highlights of recent articles of exceptional signifi cance from the cancer literature . . . . . . . . . . . . . 963
For more News and Research Watch, visit Cancer Discovery online at http://CDnews.aacrjournals.org.
In The Spotlight
Epigenetic Approaches for Chemosensitization of Refractory Diffuse Large B-Cell Lymphomas . . . . . . . . . . . . .968J.J. Steinhardt and R.B. Gartenhaus
See article, p. 1002
Resistance Emerges to Second-Generation Antiandrogens in Prostate Cancer . . . . . . . . . . . . . . .971W.G. Nelson and S. Yegnasubramanian
See article, p. 1020See article, p. 1030
Say What? The Activity of the Polyamine Biosynthesis Inhibitor Difl uoromethylornithine in Chemoprevention Is a Result of Reduced Thymidine Pools? . . . .975R.A. Casero Jr
See article, p. 1072
IN THIS ISSUE
NEWSIN BRIEF
NEWSIN DEPTH
RESEARCH WATCH
ONLINE
VIEWS
Research. on February 13, 2020. © 2013 American Association for Cancercancerdiscovery.aacrjournals.org Downloaded from
SEPTEMBER 2013�CANCER DISCOVERY | v
An F876L Mutation in Androgen Receptor Confers Genetic and Phenotypic Resistance to MDV3100 (Enzalutamide) . . . . . . . . . . . . . . . . . . . . . . 1030M. Korpal, J.M. Korn, X. Gao, D.P. Rakiec, D.A. Ruddy, S. Doshi, J. Yuan, S.G. Kovats, S. Kim, V.G. Cooke, J.E. Monahan, F. Stegmeier, T.M. Roberts, W.R. Sellers, W. Zhou, and P. ZhuPrécis: A recurring androgen receptor (AR) mutation identifi ed in enzalutamide-resistant prostate cancer cells converts enzalutamide from an AR antagonist to an AR agonist.
See commentary, p. 971
Systematic Interrogation of 3q26 Identifi es TLOC1 and SKIL as Cancer Drivers . . . . 1044D. Hagerstrand, A. Tong, S.E. Schumacher, N. Ilic, R.R. Shen, H.W. Cheung, F. Vazquez, Y. Shrestha,S.Y. Kim, A.O. Giacomelli, J. Rosenbluh, A.C. Schinzel, N.A. Spardy, D.A. Barbie, C.H. Mermel, B.A. Weir,L.A. Garraway, P. Tamayo, J.P. Mesirov, R. Beroukhim, and W.C. HahnPrécis: The coamplifi ed genes TLOC1 and SKIL cooperate to induce transformation via regulation of distinct tumor phenotypes.
Parallel RNA Interference Screens Identify EGFR Activation as an Escape Mechanism in FGFR3-Mutant Cancer . . . . . . . . . . . . . . . . . . . . . . . 1058M.T. Herrera-Abreu, A. Pearson, J. Campbell, S.D. Shnyder, M.A. Knowles, A. Ashworth, and N.C. TurnerPrécis: Activation of EGFR signaling specifi cally limits the sensitivity of FGFR3-activated bladder cancer cells to FGFR inhibitors.
Unbiased Metabolite Profi ling Indicates that a Diminished Thymidine Pool Is the Underlying Mechanism of Colon Cancer Chemoprevention by Alpha-Difl uoromethylornithine . . . . . . . . . . . . . 1072M. Witherspoon, Q. Chen, L. Kopelovich, S.S. Gross, and S.M. LipkinPrécis: The cytostatic effects of α-difl uoromethylornithine (DFMO) are attribut-able to reduced cellular thymidine levels caused by depletion of an essential cofactor of thymidine synthase.
See commentary, p. 975
Clozel and colleagues found that low-dose DNA methyltransferase (DNMT) inhibitor treatment induced DNA hypomethylation and a senescence-like phenotype in chemorefractory diffuse large B-cell lymphoma (DLBCL) cells and enhanced the sensitivity of these cells to doxorubicin. In addition, DNMT inhibition upregulated the expression of several hypermethylated genes in-cluding SMAD1 in refractory DLBCL cell lines and primary tumors, indicative of epigenetic reprogramming. SMAD1 reactivation sensitized resistant cells to growth inhibition by doxorubicin, whereas SMAD1 depletion augmented chemoresistance. Furthermore, in a phase I clinical trial of newly diagnosed, high-risk patients with DLBCL, DNMT inhibitor pretreatment prior to standard chemoimmunotherapy was well tolerated and resulted in a high rate of complete remission, supporting further investigation of this therapeutic combination in DLBCL. For details, please see the article by Clozel and colleagues on page 1002.
ON THE COVER
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• Prostate Cancers Get Nerved Up• Afatinib Approved for Advanced NSCLC• UK Launches 100,000-Genome Initiative
• Myriad Genetics Sues BRCA Diagnostic Rivals• MGN1703 Maintenance Therapy Extends PFS in Colorectal Cancer• FDA Exercises Its Authority to Regulate Tobacco Products
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2013;3:OF19-1081. Cancer Discovery 3 (9)
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