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CANCERDISCOVERY CONTENTS
ii | CANCER DISCOVERY�MARCH 2017 www.aacrjournals.org
MARCH 2017 ≠ VOLUME 7 ≠ NUMBER 3
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
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
Activating ESR1 Mutations Differentially Affect the Effi cacy 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.
Highlighted research articles . . . . . . . . . . . . . . . . . . . . . . . . 235
Important news stories affecting the community . . . . . . . . . 238
Selected highlights of recent articles of exceptional signifi cance from the cancer literature . . . . . . . . . . . . . 243
For more News and Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/content/early/by/section.
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
Debugging the Black Box . . . . . 250
J.C. Yang
See article, p. 264
Polyclonal Secondary FGFR2 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
IN THIS ISSUE
NEWSIN BRIEF
RESEARCH WATCH
ONLINE
VIEWS
RESEARCHBRIEFS
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MARCH 2017�CANCER DISCOVERY | iii
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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.
Enhancer Remodeling during Adaptive 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.
RESEARCHARTICLES
The CREBBP Acetyltransferase Is a Haploinsuffi cient 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 haploinsuffi ciency cooperates with BCL2
dysregulation to promote B-cell lymphoma.
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 follow-
ing 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 neoantigen-
harboring tumor subclones or chromosomal deletion of truncal mutations. Peptides
encoded by the eliminated MANAs induced clonal expansion of neoantigen-
specific 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 resis-
tance to immune checkpoint inhibitors. For details, please see the article by
Anagnostou, Smith, and colleagues on page 264.
ON THE COVER
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2017;7:OF9-337. Cancer Discov 7 (3)
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