BREAKING INSIGHTS

687 Highlights from Recent Cancer Literature

REVIEW

689 Novel Third-Generation EGFR Tyrosine KinaseInhibitors and Strategies to OvercomeTherapeutic Resistance in Lung CancerAyesha Murtuza, Ajaz Bulbul, John Paul Shen,Parissa Keshavarzian, Brian D. Woodward,Fernando J. Lopez-Diaz, Scott M. Lippman, andHatim Husain

CANCER RESEARCH HIGHLIGHTS

699 Multimodal Action of Mas Activation for SystemicCancer Cachexia TherapyJoseph E. Rupert, Leonidas G. Koniaris, andTeresa A. Zimmers

See related article, p. 706

701 A PETGlutamate Analogue toMeasure Cancer CellRedox State and Oxidative Stress: Promise andParadoxHsiaoju S. Lee, Austin R. Pantel, Rong Zhou, andDavid A. Mankoff

See related article, p. 853

704 ATM Inhibition Sensitizes Tumors to High-DoseIrradiationDennis Hallahan

See related article, p. 773

MOLECULAR CELL BIOLOGY

706 Mas Receptor Activation Slows Tumor Growth andAttenuates Muscle Wasting in CancerKate T. Murphy, Mohammed I. Hossain, Kristy Swiderski,Annabel Chee, Timur Naim, Jennifer Trieu,Vanessa Haynes, Suzannah J. Read, David I. Stapleton,Sarah M. Judge, Jose G. Trevino, Andrew R. Judge, andGordon S. Lynch

Significance: These findings demonstrate that MasRactivation has multiple benefits of being orexigenic, anti-cachectic, and antitumorigenic, revealing it as a potentialadjunct therapy for cancer.

See related commentary, p. 699

720 SIX2 Mediates Late-Stage Metastasis via DirectRegulation of SOX2 and Induction of a CancerStem Cell ProgramMichael U.J. Oliphant, Melanie Y. Vincent,MatthewD.Galbraith, AhwanPandey, VadymZaberezhnyy,PratyaydiptaRudra, KatherineR. Johnson, JamesC.Costello,DebashisGhosh, JamesDeGregori, JoaquinM.Espinosa, andHeide L. Ford

Significance: These findings provide novel mechanistic insightinto stemness and the metastatic outgrowth of triple-negativebreast cancer cells.

735 Inhibition of Dipeptidyl Peptidase-4 AcceleratesEpithelial–Mesenchymal Transition and BreastCancer Metastasis via the CXCL12/CXCR4/mTORAxisFan Yang, Yuta Takagaki, Yasuo Yoshitomi, Takayuki Ikeda,Jinpeng Li, Munehiro Kitada, Asako Kumagai,Emi Kawakita, Sen Shi, Keizo Kanasaki, and Daisuke Koya

Significance: These findings reveal that inhibition of DPP-4increases the metastatic potential of breast cancer. This isespecially important given the potential use of DPP-4inhibition as a therapeutic strategy for type 2 diabetes.

747 Hypermethylation of SHISA3 PromotesNasopharyngeal Carcinoma Metastasis byReducing SGSM1 StabilityJian Zhang, Ying-Qin Li, Rui Guo, Ya-Qin Wang,Pan-Pan Zhang, Xin-Ran Tang, XinWen, Xiao-HongHong,Yuan Lei, Qing-Mei He, Xiao-Jing Yang, Ying Sun, Jun Ma,and Na Liu

Significance: These findings highlight the mechanism bywhich a newly identified tumor suppressor SHISA3suppresses invasion and metastasis of nasopharyngealcarcinoma.

TUMOR BIOLOGY AND IMMUNOLOGY

760 Early Loss of Histone H2B MonoubiquitylationAlters Chromatin Accessibility and Activates KeyImmune Pathways That Facilitate Progression ofOvarian CancerJagmohan Hooda, Mari�an Novak, Matthew P. Salomon,Chikako Matsuba, Romela I. Ramos, Emily MacDuffie,Melissa Song, Michelle S. Hirsch, Jenny Lester,Vinita Parkash, Beth Y. Karlan, Moshe Oren, Dave S. Hoon,and Ronny Drapkin

Significance: Loss of RNF20 and H2Bub1 contributes totransformation of the fallopian tube epithelium and plays arole in the initiation and progression of high-grade serousovarian cancer.

February 15, 2019 � Volume 79 � Number 4

Cancer Research

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773 Deletion of Atm in Tumor but not EndothelialCells Improves Radiation Response in a PrimaryMouse Model of Lung AdenocarcinomaJordan A. Torok, Patrick Oh, Katherine D. Castle,Michael Reinsvold, Yan Ma, Lixia Luo, Chang-Lung Lee,and David G. Kirsch

Significance: These findings establish radiosensitizingtumor cells rather than endothelial cells as the primarymechanism of tumor response to high-dose radiotherapy,supporting efforts to maximize local control byradiosensitizing tumors cells.

See related commentary, p. 704

783 A Novel Form of 4-1BBL Prevents CancerDevelopment via Nonspecific Activation of CD4þ

T and Natural Killer CellsHampartsoumB.Barsoumian,Lalit Batra, PradeepShrestha,William S. Bowen, Hong Zhao, Nejat K. Egilmez,Jorge G. Gomez-Gutierrez, Esma S. Yolcu, andHaval Shirwan

Significance: This study demonstrates the unique andunexpected immunomodulatory features of SA-4-1BBL thatbridge innate and adaptive immune responses with bothpreventive and therapeutic efficacy against cancer.

795 Tumor-Associated Macrophages Enhance TumorHypoxia and Aerobic GlycolysisHoibin Jeong, Sehui Kim, Beom-Ju Hong, Chan-Ju Lee,Young-Eun Kim, Seoyeon Bok, Jung-Min Oh,Seung-Hee Gwak, Min Young Yoo, Min Sun Lee,Seock-Jin Chung, Joan Defrene, Philippe Tessier,Martin Pelletier, Hyeongrin Jeon, Tae-Young Roh,Bumju Kim, Ki Hean Kim, Ji Hyeon Ju, Sungjee Kim,Yoon-Jin Lee, Dong-Wan Kim, Il Han Kim, Hak Jae Kim,Jong-Wan Park, Yun-Sang Lee, Jae Sung Lee,Gi Jeong Cheon, Irving L. Weissman, Doo Hyun Chung,Yoon Kyung Jeon, and G-One Ahn

Significance: These findings show that tumor-associatedmacrophages can significantly modulate tumor metabolism,hindering the efficacy of anticancer therapies, includinganti-PD-L1 immunotherapy.

TRANSLATIONAL SCIENCE

807 Disruption of the Rbm38-eIF4E Complex with aSynthetic Peptide Pep8 Increases p53 ExpressionChristopher A. Lucchesi, Jin Zhang, Buyong Ma,Mingyi Chen, and Xinbin Chen

Significance: Disruption of the Rbm38-eIF4E complex viasynthetic peptides induces wild-type p53 expression,suppresses tumor growth and progression, and may serve asa novel cancer therapeutic strategy.

819 EGFR and c-MET Cooperate to EnhanceResistance to PARP Inhibitors in HepatocellularCarcinomaQiongzhu Dong, Yi Du, Hui Li, Chunxiao Liu,Yongkun Wei, Mei-Kuang Chen, Xixi Zhao, Yu-Yi Chu,Yufan Qiu, Lunxiu Qin, Hirohito Yamaguchi, andMien-Chie Hung

Significance: Regulation of PARP by the c-MET and EGFRheterodimer suggests a potentially effective combinationtherapy to sensitize HCC to PARPi.

830 Direct Targeting ofMYCN Gene Amplification bySite-Specific DNA Alkylation in NeuroblastomaHiroyuki Yoda, Takahiro Inoue, Yoshinao Shinozaki,Jason Lin, Takayoshi Watanabe, Nobuko Koshikawa,Atsushi Takatori, and Hiroki Nagase

Significance: This study presents a novel approach todrugging an amplified oncogene by showing that targetinggene amplification of MYCN suppresses MYCN expressionand neuroblastoma growth.

CONVERGENCE AND TECHNOLOGIES

841 Bicyclic Peptides as a New Modality for Imagingand Targeting of Proteins Overexpressed byTumorsMatthias Eder, Silvia Pavan, Ulrike Bauder-W€ust,Katerine van Rietschoten, Ann-Christin Baranski,Helen Harrison, Spencer Campbell, Catherine L. Stace,Edward H. Walker, Liuhong Chen, Gavin Bennett,Gemma Mudd, Ursula Schierbaum, Karin Leotta,Uwe Haberkorn, Klaus Kopka, and Daniel P. Teufel

Significance: This work demonstrates the potential ofbicyclic peptides as a platform for the development of highcontrast imaging probes for potential use in clinical cancerdiagnostics and molecularly targeted therapeutics.

853 Assessment of Tumor Redox Status through (S)-4-(3-[18F]fluoropropyl)-L-Glutamic AcidPET Imaging of System xc

� ActivityPatrick N. McCormick, Hannah E. Greenwood,Matthias Glaser, Oliver D.K. Maddocks, Thibault Gendron,Kerstin Sander, Gayatri Gowrishankar, Aileen Hoehne,Tong Zhang, Adam J. Shuhendler, David Y. Lewis,Mathias Berndt, Norman Koglin, Mark F. Lythgoe,Sanjiv S. Gambhir, Erik Årstad, and Timothy H. Witney

Significance: [18F]FSPG PET imaging provides a sensitivenoninvasive measure of tumor redox status and provides anearly marker of tumor response to therapy.

See related commentary, p. 701

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POPULATION AND PREVENTION SCIENCE

864 A Large-Cohort, Longitudinal Study DeterminesPrecancer Disease Routes across DifferentCancer TypesJessica X. Hu, Marie Helleberg, Anders B. Jensen,Søren Brunak, and Jens Lundgren

Significance: This study offers an innovative approach toexamine prediagnostic disease and cancer development in alarge national population-based setting and provides apublicly available tool to foster additional cancersurveillance research.

CORRECTIONS

873 Correction: Extracellular Matrix/IntegrinSignaling Promotes Resistance to CombinedInhibition of HER2 and PI3K in HER2þ BreastCancerAriella B. Hanker, Mónica Valeria Estrada,Giampaolo Bianchini, Preston D. Moore, Junfei Zhao,Feixiong Cheng, James P. Koch, Luca Gianni,Darren R. Tyson, Violeta S�anchez, Brent N. Rexer,Melinda E. Sanders, Zhongming Zhao,Thomas P. Stricker, and Carlos L. Arteaga

874 Correction: Kinome-Wide RNA Interference ScreenReveals a Role for PDK1 in Acquired Resistance toCDK4/6 Inhibition in ER-Positive Breast CancerValerie M. Jansen, Neil E. Bhola, Joshua A. Bauer,Luigi Formisano, Kyung-Min Lee, Katherine E. Hutchinson,Agnieszka K. Witkiewicz, Preston D. Moore,Mónica Val�eria Estrada, Violeta S�anchez, Paula G. Ericsson,Melinda E. Sanders, Paula R. Pohlmann,Michael J. Pishvaian, David A. Riddle, Teresa C. Dugger,Wenyi Wei, Erik S. Knudsen, and Carlos L. Arteaga

875 Correction: Treatment of Triple-Negative BreastCancer with TORC1/2 Inhibitors Sustains aDrug-Resistant and Notch-Dependent CancerStem Cell PopulationNeil E. Bhola, Valerie M. Jansen, James P. Koch, Hua Li,Luigi Formisano, Janice A. Williams, Jennifer R. Grandis,and Carlos L. Arteaga

876 Correction: Kinome-wide Functional ScreenIdentifies Role of PLK1 in Hormone-Independent, ER-Positive Breast CancerNeil E. Bhola, Valerie M. Jansen, Sangeeta Bafna,Jennifer M. Giltnane, Justin M. Balko, Mónica V. Estrada,Ingrid Meszoely, Ingrid Mayer, Vandana Abramson,Fei Ye, Melinda Sanders, Teresa C. Dugger,Eliezer V. Allen, and Carlos L. Arteaga

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ABOUT THE COVER

Cancer cachexia describes the muscle wasting and weakness that robs many patients withcancer of their strength and capacity to perform daily tasks and to live independently.Activation of the mitochondrial assembly receptor (MasR) had multiple benefits for tumor-bearing mice with cancer cachexia, including attenuated tumor development, reducedweight loss, slowed muscle wasting, and improved locomotor activity. MasR-mediatedprotection against muscle wasting was conferred through preservation of the large, fastmuscle fibers. For details, see article by Murphy and colleagues on page 706.

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2019;79:687-876. Cancer Res     79 (4)

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