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CANCERDISCOVERY CONTENTS
ii | CANCER DISCOVERY�SEPTEMBER 2016 www.aacrjournals.org
SEPTEMBER 2016 ≠ VOLUME 6 ≠ NUMBER 9
MET-Driven Resistance to Dual EGFR and BRAF Blockade May Be Overcome by Switching from EGFR to MET Inhibition in BRAF-Mutated Colorectal Cancer . . . . . . . . . . . . . 963
F. Pietrantonio, D. Oddo, A. Gloghini, E. Valtorta, R. Berenato, L. Barault, M. Caporale, A. Busico, F. Morano, A.V. Gualeni, A. Alessi, G. Siravegna, F. Perrone, M. Di Bartolomeo, A. Bardelli, F. de Braud, and F. Di Nicolantonio
Précis: MET amplifi cation promotes
resistance to dual EGFR and BRAF
inhibition, and a patient with resistant
metastatic colorectal cancer showed an
early response to ongoing treatment with
MET and BRAF inhibitors.
Triggering the TCR Developmental Checkpoint Activates a Therapeutically Targetable Tumor Suppressive Pathway in T-cell Leukemia . . . . . . . . . . . . . .972
A. Trinquand, N.R. dos Santos, C. Tran Quang, F. Rocchetti, B. Zaniboni, M. Belhocine, C. Da Costa de Jesus, L. Lhermitte, M. Tesio, M. Dussiot, F.-L. Cosset, E. Verhoeyen, F. Pfl umio, N. Ifrah, H. Dombret, S. Spicuglia, L. Chatenoud, D.-A. Gross, O. Hermine, E. Macintyre, J. Ghysdael, and V. Asnafi
Précis: Stimulation of T cell–receptor
signaling using anti-CD3 antibody
reactivates a lineage-specifi c negative
selection checkpoint and induces tumor
cell death in T-ALL.
See commentary, p. 946
Mechanism, Consequences, and Therapeutic Targeting of Abnormal IL15 Signaling in Cutaneous T-cell Lymphoma . . . .986
A. Mishra, K. La Perle, S. Kwiatkowski, L.A. Sullivan, G.H. Sams, J. Johns, D.P. Curphey, J. Wen, K. McConnell, J. Qi, H. Wong, G. Russo, J. Zhang, G. Marcucci, J.E. Bradner, P. Porcu, and M.A. Caligiuri
Précis: Epigenetic upregulation of IL15
induces cutaneous T-cell lymphoma by
enhancing expression of HDAC1 and
HDAC6, suggesting the potential for
treatment with specifi c HDAC inhibitors.
RESEARCHBRIEF
RESEARCHARTICLES
Highlighted research articles . . . . . . . . . . . . . . . . . . . . . . . . . 932
Important news stories affecting the community . . . . . . . . . . 936
Ten Steps to Advance Biomarker Testing . . . . . . . . . . . . . . 940
Selected highlights of recent articles of exceptional signifi cance from the cancer literature . . . . . . . . . . . . . . 941
For more News and Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/content/early/by/section.
In The Spotlight
Activating TCR Signaling to Thwart T-ALL . . . . . . . . . . . . . . . 946
F. Lemonnier and T.W. Mak
See article, p. 972
Developing EZH2-Targeted Therapy for Lung Cancer. . . . . . . 949
A.E. Frankel, X. Liu, and J.D. Minna
See article, p. 1006
Complementing T-cell Function: An Inhibitory Role of the Complement System in T-cell–Mediated Antitumor Immunity . . . . . . . . . . . 953
W. Peng, J.A. McKenzie, and P. Hwu
See article, p. 1022
Prospective
High-Throughput Testing ofNovel–Novel Combination Therapies for Cancer: An Idea Whose Time Has Come . . . . . . . . . 956
U.K. Scarlett, D.C. Chang, T.J. Murtagh, and K.T. Flaherty
IN THIS ISSUE
NEWSIN BRIEF
NEWSIN DEPTH
RESEARCH WATCH
ONLINE
VIEWS
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SEPTEMBER 2016�CANCER DISCOVERY | iii
Oncogenic Deregulation of EZH2 as an Opportunity for Targeted Therapy in Lung Cancer . . . . . . . . . . . . . . . . . . . . . . . 1006
H. Zhang, J. Qi, J.M. Reyes, L. Li, P.K. Rao, F. Li, C.Y. Lin, J.A. Perry, M.A. Lawlor, A. Federation, T. De Raedt, Y.Y. Li, Y. Liu, M.A. Duarte, Y. Zhang, G.S. Herter-Sprie, E. Kikuchi, J. Carretero, C.M. Perou, J.B. Reibel, J. Paulk, R.T. Bronson, H. Watanabe, C.F. Brainson, C.F. Kim, P.S. Hammerman, M. Brown, K. Cichowski, H. Long, J.E. Bradner, and K.-K. Wong
Précis: EZH2 overexpression drives a subset of
NSCLCs that are molecularly distinct from KRAS-
mutant and EGFR-mutant tumors and may be
vulnerable to EZH2 inhibition.
See commentary, p. 949
Autocrine Complement Inhibits IL10-Dependent T-cell–Mediated Antitumor Immunity to Promote Tumor Progression . . . . . . . . . . . . . . . . . . 1022
Y. Wang, S.-N. Sun, Q. Liu, Y.-Y. Yu, J. Guo, K. Wang, B.-C. Xing, Q.-F. Zheng, M.J. Campa, E.F. Patz Jr, S.-Y. Li, and Y.-W. He
Précis: Endogenous complement inhibits
IL10 production by CD8+ tumor infi ltrating
lymphocytes to decrease antitumor immunity and
drive tumorigenesis.
See commentary, p. 953
Dissection of the Major Hematopoietic Quantitative Trait Locus in Chromosome 6q23.3 Identifi es miR-3662 as a Player in Hematopoiesis and Acute Myeloid Leukemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1036
S.E. Maharry, C.J. Walker, S. Liyanarachchi, S. Mehta, M. Patel, M.A. Bainazar, X. Huang, M.A. Lankenau, K.W. Hoag, P. Ranganathan, R. Garzon, J.S. Blachly, D.C. Guttridge, C.D. Bloomfi eld, A. de la Chapelle, and A.-K. Eisfeld
Précis: miR-3662 contributes to the hematopoietic
differentiation phenotypes associated with the
master hematopoietic regulatory quantitative trait
locus in chromosome 6q23.3.
Genome-Wide Meta-Analyses of Breast, Ovarian, and Prostate Cancer Association Studies Identify Multiple New Susceptibility Loci Shared by at Least Two Cancer Types . . . . . . . . . . . . . 1052
S.P. Kar, J. Beesley, A. Amin Al Olama, K. Michailidou, J. Tyrer, Z. Kote-Jarai, K. Lawrenson, S. Lindstrom,
S.J. Ramus, D.J. Thompson, A.S. Kibel, A. Dansonka-Mieszkowska, A. Michael, A.K. Dieffenbach, A. Gentry-Maharaj, A.S. Whittemore, A. Wolk, A. Monteiro, A. Peixoto, A. Kierzek, A. Cox, A. Rudolph, A. Gonzalez-Neira, A.H. Wu, A. Lindblom, A. Swerdlow, A. Ziogas, A.B. Ekici, B. Burwinkel, B.Y. Karlan, B.G. Nordestgaard, C. Blomqvist, C. Phelan, C. McLean, C.L. Pearce, C. Vachon, C. Cybulski, C. Slavov, C. Stegmaier, C. Maier, C.B. Ambrosone, C.K. Høgdall, C.C. Teerlink, D. Kang, D.C. Tessier, D.J. Schaid, D.O. Stram, D.W. Cramer, D.E. Neal, D. Eccles, D. Flesch-Janys, D.R. Velez Edwards, D. Wokozorczyk, D.A. Levine, D. Yannoukakos, E.J. Sawyer, E.V. Bandera, E.M. Poole, E.L. Goode, E. Khusnutdinova, E. Høgdall, F. Song, F. Bruinsma, F. Heitz, F. Modugno, F.C. Hamdy, F. Wiklund, G.G. Giles, H. Olsson, H. Wildiers, H.-U. Ulmer, H. Pandha, H.A. Risch, H. Darabi, H.B. Salvesen, H. Nevanlinna, H. Gronberg, H. Brenner, H. Brauch, H. Anton-Culver, H. Song, H.-Y. Lim, I. McNeish, I. Campbell, I. Vergote, J. Gronwald, J. Lubiński, J.L. Stanford, J. Benítez, J.A. Doherty, J.B. Permuth, J. Chang-Claude, J.L. Donovan, J. Dennis, J.M. Schildkraut, J. Schleutker, J.L. Hopper, J. Kupryjanczyk, J.Y. Park, J. Figueroa, J.A. Clements, J.A. Knight, J. Peto, J.M. Cunningham, J. Pow-Sang, J. Batra, K. Czene, K.H. Lu, K. Herkommer, K.-T. Khaw,K. Matsuo, K. Muir, K. Offi tt, K. Chen, K.B. Moysich, K. Aittomäki, K. Odunsi, L.A. Kiemeney, L.F.A.G. Massuger, L.M. Fitzgerald, L.S. Cook, L. Cannon-Albright, M.J. Hooning, M.C. Pike, M.K. Bolla, M. Luedeke, M.R. Teixeira, M.T. Goodman, M.K. Schmidt, M. Riggan, M. Aly, M.A. Rossing, M.W. Beckmann, M. Moisse, M. Sanderson, M.C. Southey, M. Jones, M. Lush, M.A.T. Hildebrandt, M.-F. Hou, M.J. Schoemaker, M. Garcia-Closas, N. Bogdanova, N. Rahman, N.D. Le, N. Orr, N. Wentzensen, N. Pashayan, P. Peterlongo, P. Guénel, P. Brennan, P. Paulo, P.M. Webb, P. Broberg, P.A. Fasching, P. Devilee, Q. Wang, Q. Cai, Q. Li, R. Kaneva, R. Butzow, R.K Kopperud, R.K. Schmutzler, R.A. Stephenson, R.J. MacInnis, R.N. Hoover, R. Winqvist, R. Ness, R.L. Milne, R.C. Travis, S. Benlloch, S.H. Olson, S.K. McDonnell, S.S. Tworoger, S. Maia, S. Berndt, S.C. Lee, S.-H. Teo, S.N. Thibodeau, S.E. Bojesen, S.M. Gapstur, S.K. Kjær, T. Pejovic, T.L.J. Tammela, T. Dörk, T. Brüning, T. Wahlfors, T.J. Key, T.L. Edwards, U. Menon, U. Hamann, V. Mitev, V.-M. Kosma, V.W. Setiawan, V. Kristensen, V. Arndt, W. Vogel, W. Zheng, W. Sieh, W.J. Blot, W. Kluzniak, X.-O. Shu,Y.-T. Gao, F. Schumacher, M.L. Freedman, A. Berchuck,A.M. Dunning, J. Simard, C.A. Haiman, A. Spurdle, T.A. Sellers, D.J. Hunter, B.E. Henderson, P. Kraft, S.J. Chanock, F.J. Couch, P. Hall, S.A. Gayther, D.F. Easton, G. Chenevix-Trench, R. Eeles, P.D.P. Pharoah, and D. Lambrechts
Précis: Meta-analyses of multiple GWAS studies
identifi ed seven pleiotropic susceptibility loci in
three hormone-related cancers.
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CANCERDISCOVERY CONTENTS
iv | CANCER DISCOVERY�SEPTEMBER 2016 www.aacrjournals.org
Zhang, Qi, and colleagues demonstrated that overexpression of the histone methyl-
transferase EZH2 was sufficient to drive lung adenocarcinoma tumor igenesis in ap-
proximately 40% of mice. EZH2 overexpression altered chromatin structure to
disrupt normal developmental pathways, and EZH2-addicted murine tumors had
similar signaling profiles as a subset of EZH2-overexpressing human non–small cell
lung cancers (NSCLC) that were EGFR- and KRAS-wild-type. EZH2 depletion sup-
pressed the growth of EZH2-overexpressing lung adenocarcinoma cells in vitro and
in vivo, prompting the development of an enzymatic EZH2 inhibitor, JQEZ5, which
induced tumor regression and reduced H3K27me3 in mice bearing EZH2-driven tu-
mors. Together, these findings suggest that EZH2 targeting may be effective in a
subset of NSCLCs that overexpress EZH2. For details, please see the article by
Zhang, Qi, and colleagues on page 1006.
ON THE COVER
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2016;6:OF6-1067. Cancer Discov 6 (9)
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http://cancerdiscovery.aacrjournals.org/content/6/9
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