CANCER DISCOVERY CONTENTS

ii | CANCER DISCOVERY JUNE 2019 www.aacrjournals.org

JUNE 2019 ≠ VOLUME 9 ≠ NUMBER 6

A First-in-Human Study and Biomarker Analysis of NKTR-214, A Novel IL2Rbg-Biased Cytokine, in Patients with Advanced or Metastatic Solid Tumors . . . . . . .711S .-E . Bentebibel, M .E . Hurwitz, C . Bernatchez, C . Haymaker, C .W . Hudgens, H .M . Kluger, M .T . Tetzlaff, M .A . Tagliaferri, J . Zalevsky, U . Hoch, C . Fanton, S . Aung, P . Hwu, B .D . Curti, N .M . Tannir, M . Sznol, and A . DiabPrécis: NKTR-214, a human recombinant IL2 attached to releasable polyethylene glycol chains to bias against binding to the low-affinity IL2Rα chain, promotes disease stabilization and stimulates immune cell infiltration in solid tumors .

See commentary, p. 694

PARP Inhibitor Efficacy Depends on CD8+ T-cell Recruitment via Intratumoral STING Pathway Activation in BRCA-Deficient Models of Triple-Negative Breast Cancer . . . . . . . . . . . . . . . . . .722C . Pantelidou, O . Sonzogni, M . De Oliveria Taveira, A .K . Mehta, A . Kothari, D . Wang, T . Visal, M .K . Li, J . Pinto, J .A . Castrillon, E .M . Cheney, P . Bouwman, J . Jonkers, S . Rottenberg, J .L . Guerriero, G .M . Wulf, and G .I . ShapiroPrécis: PARP inhibition in BRCA-deficient TNBC tumors activates the cytosolic DNA-sensing cGAS/STING pathway to induce recruitment of CD8+ T cells to the tumor microenvironment .

Tissue-Specific Oncogenic Activity of KRASA146T . . . . . . . . . .738E .J . Poulin, A .K . Bera, J . Lu, Y .-J . Lin, S .D . Strasser, J .A . Paulo, T .Q . Huang, C . Morales, W . Yan, J . Cook, J .A . Nowak, D .K . Brubaker, B .A . Joughin, C .W . Johnson, R .A . DeStefanis, P .C . Ghazi, S . Gondi, T .E . Wales, R .E . Iacob, L . Bogdanova, J .J . Gierut, Y . Li, J .R . Engen, P .A . Perez-Mancera, B .S . Braun, S .P . Gygi, D .A . Lauffenburger, K .D . Westover, and K .M . HaigisPrécis: Structural biology, mass spectrometry, and mouse modeling demonstrate the variable strength and tissue-specific effects of KRAS mutants in promoting cancer .

See commentary, p. 696

RESEARCH BRIEF

RESEARCH ARTICLES

Highlighted research articles . . . . . . . . . . . . . . . . . . . . . . . . 681

Important news stories affecting the community . . . . . . . . . 684

PD-1 Blockade in GBM: Uncovering Response Clues . . . 687

Selected highlights of recent articles of exceptional significance from the cancer literature . . . . . . . . . . . . . 689

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

In The Spotlight

Back to the Future: Rethinking and Retooling IL2 in the Immune Checkpoint Inhibitor Era . . . . . . 694R .J . Sullivan

See article, p. 711

RAS Mutations Are Not Created Equal . . . . . . . . . . . . . . . . . 696G .A . Hobbs and C .J . Der

See article, p. 738

Kinase Networks Regulate Metabolism: I’D(H1) Never Have Guessed! . . . . . . . . . . . . . . . . . 699S . Horton and B .J .P . Huntly

See article, p. 756

Tumor Neurobiology and the War of Nerves in Cancer . . . . . . .702S . Faulkner, P . Jobling, B . March, C .C . Jiang, and H . Hondermarck

IN THIS ISSUE

NEWS IN BRIEF

NEWS IN DEPTH

RESEARCH WATCH

ONLINE

VIEWS

MINI REVIEW

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JUNE 2019 CANCER DISCOVERY | iii

Mutant and Wild-Type Isocitrate Dehydrogenase 1 Share Enhancing Mechanisms Involving Distinct Tyrosine Kinase Cascades in Cancer . . . . . . . . . . . 756D . Chen, S . Xia, M . Wang, R . Lin, Y . Li, H . Mao, M . Aguiar, C .A . Famulare, A .H . Shih, C .W . Brennan, X . Gao, Y . Pan, S . Liu, J . Fan, L . Jin, L . Song, A . Zhou, J . Mukherjee, R .O . Pieper, A . Mishra, J . Peng, M . Arellano, W .G . Blum, S . Lonial, T .J . Boggon, R .L . Levine, and J . ChenPrécis: Two distinct oncogenic tyrosine kinase cascades promote the activation of wild-type and mutant IDH1 in diverse cancers through direct and indirect phosphorylation of the Y42 and Y341 residues .

See commentary, p. 699

Cytokine-Regulated Phosphorylation and Activation of TET2 by JAK2 in Hematopoiesis . . . . . . . . . . . . . . . . . . . . . . . 778J .J . Jeong, X . Gu, J . Nie, S . Sundaravel, H . Liu, W .-L . Kuo, T .D . Bhagat, K . Pradhan, J . Cao, S . Nischal, K .L . McGraw, S . Bhattacharyya, M .R . Bishop, A . Artz, M .J . Thirman, A . Moliterno, P . Ji, R .L . Levine, L .A . Godley, U . Steidl, J .J . Bieker, A .F . List, Y . Saunthararajah, C . He, A . Verma, and A . WickremaPrécis: JAK2-mediated phosphorylation and activation of TET2 increases TET2 DNA hydroxymethylation activity during hematopoietic differentiation and in myeloproliferative disease .

A Recurrent Activating Missense Mutation in Waldenström Macroglobulinemia Affects the DNA Binding of the ETS Transcription Factor SPI1 and Enhances Proliferation . . . . . 796D . Roos-Weil, C . Decaudin, M . Armand, V . Della-Valle, M .K . Diop, H . Ghamlouch, V . Ropars, C . Hérate, D . Lara, E . Durot, R . Haddad, E . Mylonas, F . Damm, F . Pfl umio, B . Stoilova, M . Metzner, O . Elemento, P . Dessen, V . Camara-Clayette, F .-L . Cosset, E . Verhoeyen, V . Leblond, V . Ribrag, P . Cornillet-Lefebvre, P . Rameau, N . Azar, F . Charlotte, P . Morel, J .-B . Charbonnier, P . Vyas, T . Mercher, S . Aoufouchi,N . Droin, C . Guillouf, F . Nguyen-Khac, and O .A . BernardPrécis: A mutation of SPI1 that is recurrent in Waldenström macroglobulinemia alters the DNA binding properties of SPI1 to activate genes typically regulated by other ETS transcription factors and confer a growth advantage .

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Bentebibel, Hurwitz, Bernatchez, and colleagues report a first-in-human phase I study to evaluate the safety and activity of NKTR-214 (bempegaldesleukin), a human recombinant IL2 conjugated to slowly releasable polyethylene glycol chains that bias binding to the intermediate-affinity IL2Rbg complex instead of the low-affinity IL2Rα chain . In heavily pretreated patients with advanced solid tumors, NKTR-214 was well tolerated, and the best overall response was stable disease in 14 of 26 evaluable patients (54%) . NKTR-214 treatment induced activation and proliferation of immune cells in peripheral blood, and comparison of baseline and on-treatment tumor biopsies revealed that NKTR-214 increased T-cell activation signa-tures, CD8+ T-cell infiltration, and T-cell clonality . These findings suggest that NKTR-214 not only has immunostimulatory activity but may be a safer alternative to high-dose un-conjugated IL2, making it an attractive candidate for combination immunotherapy strat-egies . For details, please see the article by Bentebibel, Hurwitz, Bernatchez, and colleagues on page 711 .

ON THE COVER

disease in 14 of 26 evaluable patients (54%) . NKTR-214 treatment induced activation

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2019;9:OF8-811. Cancer Discov     9 (6)

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