CANCER DISCOVERY CONTENTS

ii | CANCER DISCOVERY FEBRUARY 2019 www.aacrjournals.org

FEBRUARY 2019 ≠ VOLUME 9 ≠ NUMBER 2

T. Hembrough, R.J. Nagy, R.B. Lanman, S.M. Larson, N. Pandit-Taskar, H. Schöder, C.A. Iacobuzio-Donahue, D.H. Ilson, W.A. Weber, M.F. Berger, E. de Stanchina, B.S. Taylor, J.S. Lewis, D.B. Solit, J.A. Carrasquillo, M. Scaltriti, N. Schultz, and Y.Y. JanjigianPrécis: Coamplification of EGFR and ERBB2 is associated with afatinib response in patients with trastuzumab-refractory esophagogastric cancer, whereas selection for MET amplification or loss of EGFR amplification is associated with resistance.

See commentary, p. 166

BRCA Reversion Mutations in Circulating Tumor DNA Predict Primary and Acquired Resistance to the PARP Inhibitor Rucaparib in High-Grade Ovarian Carcinoma . . . 210K.K. Lin, M.I. Harrell, A.M. Oza, A. Oaknin, I. Ray-Coquard, A.V. Tinker, E. Helman, M.R. Radke, C. Say, L-T. Vo, E. Mann, J.D. Isaacson, L. Maloney, D.M. O’Malley, S.K. Chambers, S.H. Kaufmann, C.L. Scott, G.E. Konecny, R.L. Coleman, J.X. Sun, H. Giordano, J.D. Brenton, T.C. Harding, I.A. McNeish, and E.M. SwisherPrécis: Analysis of cfDNA from 112 patients with high-grade ovarian carcinoma showed that BRCA reversion mutations may be associated with reduced clinical benefit from the PARP inhibitor rucaparib.

PPT1 Promotes Tumor Growth and Is the Molecular Target of Chloroquine Derivatives in Cancer . . . . . . . . . . . . 220V.W. Rebecca, M.C. Nicastri, C. Fennelly, C.I. Chude, J.S. Barber-Rotenberg, A. Ronghe, Q. McAfee, N.P. McLaughlin, G. Zhang, A.R. Goldman, R. Ojha, S. Piao, E. Noguera-Ortega, A. Martorella, G.M. Alicea, J.J. Lee, L.M. Schuchter, X. Xu, M. Herlyn, R. Marmorstein, P.A. Gimotty, D.W. Speicher, J.D. Winkler, and R.K. AmaravadiPrécis: Chloroquine derivatives exert their antiautophagic and antitumor effects by binding palmitoyl-protein thioesterase 1 (PPT1) and inhibiting its enzymatic activity.

Cells Lacking the RB1 Tumor Suppressor Gene Are Hyperdependent on Aurora B Kinase for Survival . . . . . 230M.G. Oser, R. Fonseca, A.A. Chakraborty, R. Brough, A. Spektor, R.B. Jennings, A. Flaifel, J.S. Novak, A. Gulati, E. Buss, S.T. Younger, S.K. McBrayer, G.S. Cowley, D.M. Bonal, Q.-D. Nguyen, L. Brulle-Soumare, P. Taylor, S. Cairo, C.J. Ryan, E.J. Pease,

RESEARCH ARTICLES

Highlighted research articles . . . . . . . . . . . . . . . . . . . . . . . . 151

Important news stories affecting the community . . . . . . . . . 156

Selected highlights of recent articles of exceptional significance from the cancer literature . . . . . . . . . . . . . 161

For more News and Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.

In The Spotlight

Variety Is the Spice of Life, but Maybe Not in Gastroesophageal Adenocarcinomas . . . . . . . . . . . . . 166S.J. Klempner and D.V.T. Catenacci

See article, p. 199

Drugging RB1 Deficiency: Synthetic Lethality with Aurora Kinases . . 169F.A. Dick and S.S-C. Li

See article, p. 230See article, p. 248

Two Birds with One Stone: Therapeutic Targeting of IL1α Signaling Pathways in Pancreatic Ductal Adenocarcinoma and the Cancer-Associated Fibroblasts . . . . . . . 173J. Ling and P.J. Chiao

See article, p. 282

Insights into Molecular Classifications of Triple-Negative Breast Cancer: Improving Patient Selection for Treatment . . . . . .176A.C. Garrido-Castro, N.U. Lin, and K. Polyak

EGFR and MET Amplifications Determine Response to HER2 Inhibition in ERBB2-Amplified Esophagogastric Cancer . . . . . . 199F. Sanchez-Vega, J.F. Hechtman, P. Castel, G.Y. Ku, Y. Tuvy, H. Won, C.J. Fong, N. Bouvier, G.J. Nanjangud, J. Soong, E. Vakiani, M. Schattner, D.P. Kelsen, R.A. Lefkowitz, K. Brown, M.E. Lacouture, M. Capanu, M. Mattar, B. Qeriqi, F. Cecchi, Y. Tian,

IN THIS ISSUE

NEWS IN BRIEF

RESEARCH WATCH

ONLINE

VIEWS

REVIEW

RESEARCH BRIEFS

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FEBRUARY 2019 CANCER DISCOVERY | iii

K. Maratea, J. Travers, D.E. Root, S. Signoretti, D. Pellman, S. Ashton, C.J. Lord, S.T. Barry, and W.G. Kaelin JrPrécis: A CRISPR/Cas9 screen identifi es a synthetic lethal relationship between RB1 and AURKB loss in SCLC cells.

See commentary, p. 169

Aurora A Kinase Inhibition Is Synthetic Lethal with Loss of the RB1 Tumor Suppressor Gene . . . . . . . . . . . . . . . . . . . . 248X. Gong, J. Du, S.H. Parsons, F.F. Merzoug, Y. Webster,P.W. Iversen, L.-C. Chio, R.D. Van Horn, X. Lin, W. Blosser, B. Han, S. Jin, S. Yao, H. Bian, C. Ficklin, L. Fan, A. Kapoor, S. Antonysamy, A.M. Mc Nulty, K. Froning, D. Manglicmot, A. Pustilnik, K. Weichert,S.R. Wasserman, M. Dowless, C. Marugán, C. Baquero,M.J. Lallena, S.W. Eastman,Y.-H. Hui, M.Z. Dieter, T. Doman, S. Chu, H.-R. Qian, X.S. Ye, D.A. Barda, G.D. Plowman, C. Reinhard, R.M. Campbell, J.R. Henry, and S.G. BuchananPrécis: A screen of cell-cycle inhibitors reveals that RB1-mutant cancer cells are selectively dependent on Aurora kinase A.See commentary, p. 169

EIF1AX and RAS Mutations Cooperate to Drive Thyroid Tumorigenesis through ATF4 and c-MYC . . . . . . . . . . . . . . . . . . . . . 264G.P. Krishnamoorthy, N.R. Davidson, S.D. Leach, Z. Zhao, S.W. Lowe, G. Lee, I. Landa, J. Nagarajah, M. Saqcena, K. Singh, H.-G. Wendel, S. Dogan, P.P. Tamarapu, J. Blenis, R.A. Ghossein, J.A. Knauf, G. Rätsch, and J.A. FaginPrécis: The EIF1AX-A113spl mutation results in an alternatively spliced transcript that cooperates with RAS mutations to stabilize MYC, activate mTOR, and promote tumorigenesis.

IL1-Induced JAK/STAT Signaling Is Antagonized by TGFβ to Shape CAF Heterogeneity in Pancreatic Ductal Adenocarcinoma . . . . . . . . . . . . . . . . . . . . 282G. Biffi , T.E. Oni, B. Spielman, Y. Hao, E. Elyada, Y. Park, J. Preall, and D.A. TuvesonPrécis: TGFβ antagonizes IL1-driven JAK/STAT activation, which induces an infl ammatory pancreatic ductal adenocarcinoma cancer–associated fi broblast (CAF) phenotype, to promote CAF heterogeneity.

See commentary, p. 173

Corrections

Correction: Drug-Resistant Brain Metastases: A Role for Pharmacology, Tumor Evolution, and Too-Late Therapy . . . . . . . . . 302T. Stricker and C.L. Arteaga

Correction: An Acquired HER2T798I

Gatekeeper Mutation Induces Resistance to Neratinib in a Patient with HER2 Mutant–Driven Breast Cancer . . . . . . . . . . 303A.B. Hanker, M.R. Brewer, J.H. Sheehan, J.P. Koch, G.R. Sliwoski, R. Nagy, R. Lanman, M.F. Berger, D.M. Hyman, D.B. Solit, J. He, V. Miller, R.E. Cutler Jr, A.S. Lalani, D. Cross, C.M. Lovly, J. Meiler, and C.L. Arteaga

Correction: Neoadjuvant Trials in ER+ Breast Cancer: A Tool for Acceleration of Drug Development and Discovery. . . . . . 304A.L. Guerrero-Zotano and C.L. Arteaga

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Aurora kinase A (AURKA) and Aurora kinase B (AURKB) were found to be syn-thetic lethal with RB1 loss using a “gene–gene” interaction CRISPR/Cas9-based screening approach initiated by Oser and colleagues and a “gene–drug” interac-tion approach involving a screen of cell-cycle inhibitors performed by Gong, Du, Parsons, and colleagues. Both an AURKB-specific inhibitor, AZD2811, and the developed AURKA-specific inhibitor, LY3295668, specifically eliminated RB1-mutant but not RB1–wild-type cells and had in vivo efficacy against RB1-mutant tumors. Mechanistic studies suggested that RB1 and AURKA or AURKB have partially redundant roles in mitosis, explaining their synthetic lethal interaction. These findings suggest a potential therapeutic vulnerability caused by RB1 loss and a possible way forward for treatment of RB1-mutant tumors. For details, please see the article by Oser and col-leagues on page 230 and the article by Gong, Du, Parsons, and colleagues on page 248.

ON THE COVER

A.L. Guerrero-Zotano and C.L. Arteaga

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