CANCER DISCOVERY CONTENTS

ii | CANCER DISCOVERY MAY 2019 www.aacrjournals.org

MAY 2019 ≠ VOLUME 9 ≠ NUMBER 5

Engineering Multidimensional Evolutionary Forces to Combat Cancer . . . . . . . . . . . . . . . 587C .E . McCoach and T .G . Bivona

Patient-Driven Discovery, Therapeutic Targeting, and Post-Clinical Validation of a Novel AKT1 Fusion–Driven Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . 605E .K . Slotkin, D . Diolaiti, N .N . Shukla, F .S . Dela Cruz, J .J . Clark, G . Gundem, V .D . Yellapantula, M .F . Levine, D . You, P . Ma, S . Pachhal, G . Ibanez Sanchez, R . Benayed, A .A . Jungbluth, L .M . Smyth, A . Mauguen, I . Gushterova, H . Ding, L . Spraggon, R . Darnell, A . Califano, M . Ladanyi, E . Papaemmanuil, A .L . Kung, D .M . Hyman, and S .S . RobertsPrécis: The response to AKT inhibition in a pediatric patient with a LAMTOR1–AKT1 fusion confirms the AKT1 fusion as an oncogenic driver, and subsequent characterization of the fusion suggests potential ways to overcome resistance .

A Stromal Lysolipid–Autotaxin Signaling Axis Promotes Pancreatic Tumor Progression . . . 617F .R . Auciello, V . Bulusu, C . Oon, J . Tait-Mulder, M . Berry, S . Bhattacharyya, S . Tumanov, B .L . Allen-Petersen, J . Link, N .D . Kendsersky, E . Vringer, M . Schug, D . Novo, R .F . Hwang, R .M . Evans, C . Nixon, C . Dorrell, J .P . Morton, J .C . Norman, R .C . Sears, J .J . Kamphorst, and M .H . ShermanPrécis: Lysophosphatidylcholines secreted by activated stromal fibroblasts support pancreatic cancer cell proliferation and migration via autotaxin-mediated production of lysophosphatidic acid .

See commentary, p. 578

REVIEW

RESEARCH BRIEFS

Highlighted research articles . . . . . . . . . . . . . . . . . . . . . . . . 565

Important news stories affecting the community . . . . . . . . . 568

Targeting MCL1, Companies Aim to Unblock Apoptosis . . . . . 572

Selected highlights of recent articles of exceptional significance from the cancer literature . . . . . . . . . . . . . 573

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

In The Spotlight

A FATal Combination: Fibroblast-Derived Lipids and Cancer-Derived Autotaxin Promote Pancreatic Cancer Growth . . . . . . . . . . . . . . . . . . . 578G . Biffi and D .A . Tuveson

See article, p. 617

Metabolic Checkpoint of Immune Cells in Melanoma Brain Metastases . . . . . . . . . . . . 581C .A . Egelston and K . Margolin

See article, p. 628

Delivering a STINGing Blow to Small Cell Lung Cancer via Synergistic Inhibition of DNA-Damage Response and Immune-Checkpoint Pathways . . . . . . . . . . . . . . . . . . . . . 584J .B . Hiatt and D . MacPherson

See article, p. 646

IN THIS ISSUE

NEWS IN BRIEF

NEWS IN DEPTH

RESEARCH WATCH

ONLINE

VIEWS

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MAY 2019 CANCER DISCOVERY | iii

Molecular Profi ling Reveals Unique Immune and Metabolic Features of Melanoma Brain Metastases . . . . . . . . . . . . . . . . . . . . 628G .M . Fischer, A . Jalali, D .A . Kircher, W .-C . Lee, J .L . McQuade, L .E . Haydu, A .Y . Joon, A . Reuben, M .P . de Macedo, F .C .L . Carapeto, C . Yang, A . Srivastava, C .R . Ambati, A . Sreekumar, C .W . Hudgens, B . Knighton, W . Deng, S .D . Ferguson, H .A . Tawbi, I .C . Glitza, J .E . Gershenwald, Y .N . Vashisht Gopal, P . Hwu, J .T . Huse, J .A . Wargo, P .A . Futreal, N . Putluri, A .J . Lazar, R .J . DeBerardinis, J .R . Marszalek, J . Zhang, S .L . Holmen, M .T . Tetzlaff, and M .A . DaviesPrécis: Comprehensive molecular profi ling of patient-matched melanoma brain metastases and extracranial metastases unveil signifi cant differences between these two metastatic populations .

See commentary, p. 581

Targeting DNA Damage Response Promotes Antitumor Immunity through STING-Mediated T-cell Activation in Small Cell Lung Cancer . . . . . . . . . . . . . . . 646T . Sen, B .L . Rodriguez, L . Chen, C .M . Della Corte, N . Morikawa, J . Fujimoto, S . Cristea, T . Nguyen, L . Diao, L . Li, Y . Fan, Y . Yang, J . Wang, B .S . Glisson, I .I . Wistuba, J . Sage, J .V . Heymach, D .L . Gibbons, and L .A . ByersPrécis: Pharmacologic inhibition of PARP and CHK1 increases expression of PD-L1 and

RESEARCHARTICLES

potentiates the antitumor effects of PD-L1 blockade via activation of the innate immune STING pathway .

See commentary, p. 584

BCL6 Evolved to Enable Stress Tolerance in Vertebrates and Is Broadly Required by Cancer Cells to Adapt to Stress . . . 662T .M . Fernando, R . Marullo, B . Pera Gresely, J .M . Phillip, S .N . Yang, G . Lundell-Smith, I . Torregroza, H . Ahn, T . Evans, B . Győrffy, G .G . Privé, M . Hirano, A .M . Melnick, and L . CerchiettiPrécis: An evolutionarily conserved HSF1–BCL6 axis mediates stress adaptation across vertebrates and promotes tolerance to chemotherapy in cancer cells, in part via repression of the transcription factor TOX .

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Sen and colleagues showed that treatment of human small cell lung cancer (SCLC) cell lines with inhibitors of the DNA damage response (DDR) components CHK1 and PARP resulted in increased expression of PD-L1 . Further, inhibition of either CHK1 or PARP in immunocompetent genetically engineered mouse models (GEMM) of SCLC resulted in increased levels of cytosolic DNA, which activates the cGAS–STING innate immune signaling pathway to induce IRF3 activation and subse-quently drive IFNβ-mediated increases in PD-L1 expression and T-cell recruitment in SCLC GEMMs . Consistent with these findings, treatment with a CHK1 or PARP inhibitor enhanced the efficacy of anti–PD-L1 therapy and resulted in SCLC tumor regression in vivo . Together, these findings suggest that combined targeting of DDR proteins and immune checkpoint blockade is a potential therapeutic strategy for patients with SCLC . For details, please see the article by Sen and colleagues on page 646 .

ON THE COVER

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2019;9:OF6-679. Cancer Discov     9 (5)

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