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CANCER
DISCOVERY
MARCH 2017
≠
VOLUME 7
≠
CONTENTS
NUMBER 3
IN THIS Highlighted research
ISSUE articles . . . . . . . . . . . . . . . . . . . . . . . . 235
NEWS Important news stories
IN BRIEF affecting the community . . . . . . . . . 238
Précis: Patients with FGFR2 fusion–
positive ICC develop resistance to
the FGFR inhibitor BGJ398 through
acquisition of multiple recurrent point
mutations in FGFR2 that can be overcome
by structurally distinct FGFR inhibitors.
See commentary, p. 248
RESEARCH Selected highlights of recent articles
WATCH of exceptional significance from
the cancer literature . . . . . . . . . . . . . 243
ONLINE For more News and Research Watch,
visit Cancer Discovery online at
http://cancerdiscovery.aacrjournals.org/
content/early/by/section.
VIEWS In The Spotlight
Gatekeeper Mutations and
Intratumoral Heterogeneity
in FGFR2-Translocated
Cholangiocarcinoma . . . . . . . . . . 248
E.C. Smyth, I.S. Babina, and N.C. Turner
See article, p. 252
Evolution of Neoantigen
Landscape during Immune
Checkpoint Blockade in
Non–Small Cell Lung Cancer . . . 264
V. Anagnostou, K.N. Smith, P.M. Forde,
N. Niknafs, R. Bhattacharya, J. White,
T. Zhang, V. Adleff, J. Phallen, N. Wali,
C. Hruban, V.B. Guthrie, K. Rodgers,
J. Naidoo, H. Kang, W. Sharfman,
C. Georgiades, F. Verde, P. Illei, Q.K. Li,
E. Gabrielson, M.V. Brock, C.A. Zahnow,
S.B. Baylin, R.B. Scharpf, J.R. Brahmer,
R. Karchin, D.M. Pardoll, and
V.E. Velculescu
Précis: Acquired resistance to immune
checkpoint inhibitors is accompanied by
elimination of a subset of immunogenic
mutation-associated neoantigens.
See commentary, p. 250
Debugging the Black Box . . . . . 250
J.C. Yang
See article, p. 264
RESEARCH Polyclonal Secondary FGFR2
BRIEFS Mutations Drive Acquired
Resistance to FGFR Inhibition
in Patients with FGFR2
Fusion–Positive
Cholangiocarcinoma . . . . . . . . . . 252
L. Goyal, S.K. Saha, L.Y. Liu, G. Siravegna,
I. Leshchiner, L.G. Ahronian, J.K. Lennerz,
P. Vu, V. Deshpande, A. Kambadakone,
B. Mussolin, S. Reyes, L. Henderson,
J.E. Sun, E.E. Van Seventer, J.M. Gurski Jr,
S. Baltschukat, B. Schacher-Engstler,
L. Barys, C. Stamm, P. Furet, D.P. Ryan,
J.R. Stone, A.J. Iafrate, G. Getz,
D. Graus Porta, R. Tiedt, A. Bardelli, D. Juric,
R.B. Corcoran, N. Bardeesy, and A.X. Zhu
ii | CANCER DISCOVERYMARCH 2017
Activating ESR1 Mutations
Differentially Affect the Efficacy
of ER Antagonists . . . . . . . . . . . . . 277
W. Toy, H. Weir, P. Razavi, M. Lawson,
A.U. Goeppert, A.M. Mazzola, A. Smith,
J. Wilson, C. Morrow, W.L. Wong,
E. De Stanchina, K.E. Carlson,
T.S. Martin, S. Uddin, Z. Li, S. Fanning,
J.A. Katzenellenbogen, G. Greene,
J. Baselga, and S. Chandarlapaty
Précis: ESR1 mutations were characterized
and assessed for constitutive activity and
sensitivity to ER antagonists.
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OTX2 Activity at Distal Regulatory
Elements Shapes the Chromatin
Landscape of Group 3
Medulloblastoma . . . . . . . . . . . . . . . . . . . . . 288
G. Boulay, M.E. Awad, N. Riggi, T.C. Archer,
S. Iyer, W.E. Boonseng, N.E. Rossetti, B. Naigles,
S. Rengarajan, A. Volorio, J.C. Kim, J.P. Mesirov,
P. Tamayo, S.L. Pomeroy, M.J. Aryee, and
M.N. Rivera
Précis: OTX2 is a pioneer transcription factor
that occupies the majority of active enhancers in
Group 3 medulloblastoma and, in cooperation
with NEUROD1, maintains their activation state.
The CREBBP Acetyltransferase Is a
Haploinsufficient Tumor Suppressor
in B-cell Lymphoma . . . . . . . . . . . . . . . . . . 322
J. Zhang, S. Vlasevska, V.A. Wells, S. Nataraj,
A.B. Holmes, R. Duval, S.N. Meyer, T. Mo, K. Basso,
P.K. Brindle, S. Hussein, R. Dalla-Favera, and
L. Pasqualucci
Précis: CREBBP regulates germinal center B-cell
enhancers for normal B-cell differentiation, and
CREBBP haploinsufficiency cooperates with BCL2
dysregulation to promote B-cell lymphoma.
RESEARCH Enhancer Remodeling during Adaptive
ARTICLES Bypass to MEK Inhibition Is Attenuated
by Pharmacologic Targeting of the
P-TEFb Complex . . . . . . . . . . . . . . . . . . . . . 302
J.S. Zawistowski, S.M. Bevill, D.R. Goulet,
T.J. Stuhlmiller, A.S. Beltran, J.F. Olivares-Quintero,
D. Singh, N. Sciaky, J.S. Parker, N.U. Rashid,
X. Chen, J.S. Duncan, M.C. Whittle, S.P. Angus,
S.H. Velarde, B.T. Golitz, X. He, C. Santos, D.B. Darr,
K. Gallagher, L.M. Graves, C.M. Perou, L.A. Carey,
H.S. Earp, and G.L. Johnson
Précis: Treatment with the MEK inhibitor trametinib
induces an epigenetic upregulation of receptor
tyrosine kinases to promote resistance in TNBC
cells that can be overcome by inhibition of BRD4 or
P-TEFb.
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ON THE
COVER
To evaluate changes in tumor neoantigens during immune checkpoint
blockade, Anagnostou, Smith, and colleagues performed whole-exome
sequencing of pretreatment and post-progression tumor samples from
patients with non–small cell lung cancer who developed resistance following treatment with anti–PD-1 or anti–PD-1/anti–CTLA-4. Loss of a subset
of candidate mutation-associated neoantigens (MANA) was associated with the
emergence of acquired resistance and occurred via elimination of neoantigenharboring tumor subclones or chromosomal deletion of truncal mutations. Peptides
encoded by the eliminated MANAs induced clonal expansion of neoantigenspecific T cells, indicative of functional immune responsiveness, and loss of
these MANAs correlated with reduced T-cell receptor clonality. These findings
suggest that immune editing of tumor neoantigens may promote acquired resistance to immune checkpoint inhibitors. For details, please see the article by
Anagnostou, Smith, and colleagues on page 264.
MARCH 2017CANCER DISCOVERY | iii
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7 (3)
Cancer Discov 2017;7:OF9-337.
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