CANCER DISCOVERY CONTENTS...iv | CANCER DISCOVERY DECEMBER 2013 CANCER DISCOVERY CONTENTS DECEMBER 2013 ≠ VOLUME 3 ≠ NUMBER 12 What a Tangled Web We Weave: Emerging Resistance

iv | CANCER DISCOVERY�DECEMBER 2013 www.aacrjournals.org

CANCERDISCOVERY CONTENTSDECEMBER 2013 ≠ VOLUME 3 ≠ NUMBER 12

What a Tangled Web We Weave: Emerging Resistance Mechanisms to Inhibition of the Phosphoinositide 3-Kinase Pathway . . . . . . . . . . . . . . 1345

S.J. Klempner, A.P. Myers, and L.C. Cantley

Activation of the PD-1 Pathway Contributes to Immune Escape in EGFR-Driven Lung Tumors . . . 1355E.A. Akbay, S. Koyama, J. Carretero, A. Altabef, J.H. Tchaicha, C.L. Christensen, O.R. Mikse, A.D. Cherniack, E.M. Beauchamp, T.J. Pugh, M.D. Wilkerson, P.E. Fecci, M. Butaney, J.B. Reibel, M. Soucheray, T.J. Cohoon,P.A. Janne, M. Meyerson, D.N. Hayes, G.I. Shapiro, T. Shimamura, L.M. Sholl, S.J. Rodig, G.J. Freeman, P.S. Hammerman, G. Dranoff, and K.-K. Wong

Précis: EGFR pathway activation promotes tumor immune evasion in NSCLC via induction of PD-1, PD-L1, and immunosuppressive, tumor-promoting cytokines.

See commentary, p. 1330

A Drug Repositioning Approach Identifi es Tricyclic Antidepressants as Inhibitors of Small Cell Lung Cancer and Other Neuroendocrine Tumors . . . . . . 1364N.S. Jahchan, J.T. Dudley, P.K. Mazur, N. Flores,D. Yang, A. Palmerton, A.-F. Zmoos, D. Vaka, K.Q.T. Tran, M. Zhou, K. Krasinska,J.W. Riess, J.W. Neal, P. Khatri, K.S. Park, A.J. Butte, and J. Sage

Précis: Clinically available drugs that dis-rupt neurotransmitter-induced G protein-coupled receptor signaling inhibit growth of tumor types with neuroendocrine features.

See commentary, p. 1333

Hypoxia Induces Phenotypic Plasticity and Therapy Resistance in Melanoma via the Tyrosine Kinase Receptors ROR1 and ROR2 . . . . . . . . . . . . . . . . . .1378M.P. O’Connell, K. Marchbank, M.R. Webster, A.A. Valiga, A. Kaur, A. Vultur, L. Li, M. Herlyn,J. Villanueva, Q. Liu, X. Yin, S. Widura, J. Nelson,N. Ruiz, T.C. Camilli, F.E. Indig, K.T. Flaherty,J.A. Wargo, D.T. Frederick, Z.A. Cooper, S. Nair,R.K. Amaravadi, L.M. Schuchter, G.C. Karakousis, W. Xu, X. Xu, and A.T. Weeraratna

Précis: WNT5A signaling promotes a pheno-type switch to more invasive, BRAF inhibitor–resistant melanomas in response to hypoxia via reciprocal regulation of ROR1 and ROR2.

MINI REVIEW

RESEARCHBRIEF

RESEARCHARTICLES

Highlighted research articles . . . . . . . . . . . . . . . . . . . . . . . .1317

Important news stories affecting the community . . . . . . . . . . . . . . . . . . . 1320

Q&A: Elizabeth Blackburn on Telomerase and Tumors . . . 1323

A Role for Aspirin in Cancer Prevention? . . . . . . . . . . . .1324

Selected highlights of recent articles of exceptional signifi cance from the cancer literature . . . . . . . . . . . . 1325

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

In The Spotlight

Dynamic Interplay of Oncogenes and T Cells Induces PD-L1 in the Tumor Microenvironment . . . . . . . . . . . 1330

A.J. Rech and R.H. Vonderheide

See article, p. 1355

Teaching an Old Dog New Tricks: Drug Repositioning in Small Cell Lung Cancer . . . . . . . . . . . . . . . . . 1333

J. Wang and L.A. Byers

See article, p. 1364

Personalized Therapy for Acute Myeloid Leukemia . . . . . . . . . . . 1336

C.S. Hourigan and J.E. Karp

See article, p. 1416

In Focus

A Systems Biology Approach to Personalizing Therapeutic Combinations . . . . . . . . . . . . . . . . 1339

L.N. Kwong, T.P. Heffernan, and L. Chin

IN THIS ISSUE

NEWSIN BRIEF

NEWSIN DEPTH

RESEARCH WATCH

ONLINE

VIEWS

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DECEMBER 2013�CANCER DISCOVERY | v

Akbay and colleagues found that EGFR activation in non–small cell lung

cancer (NSCLC) resulted in an immunosuppressive microenvironment

characterized by upregulation of programmed cell death 1 (PD-1) and its

ligand PD-L1, reduction of CD8+ cytotoxic T cells, and induction of tumor-

promoting cytokines. PD-1 blockade suppressed EGFR-driven NSCLC

growth via increased T-cell infiltration and improved cytotoxic T-cell func-

tion, as well as reduced expression of immunosuppressive cytokines. PD-L1 induc-

tion in human NSCLC cells was dependent on EGFR activation, as treatment with

EGFR kinase inhibitors decreased PD-L1 levels. These results define a non–cell-

autonomous role of oncogenic EGFR in promoting immune evasion in lung cancer

and suggest that dual inhibition of EGFR and PD-1 may be effective in EGFR-mutant

NSCLC. For details, please see the article by Akbay and colleagues on page 1355.

ON THE COVER

AC icon indicates Author Choice

For more information please visit http://www.aacrjournals.org

For more News and Research Watch, visit Cancer Discovery online at http://CDnews.aacrjournals.org. Online-only News stories include

the following:

• Checkpoint Inhibitor Shows Promise in Smokers

• T-DM1 Aids Patients with Advanced Breast Cancer

• Decade-Long Survival Possible after Ipilimumab

• Antibody–Drug Conjugate May Inhibit Pancreatic Cancer

• Ramucirumab Takes Steps Forward in Gastric Cancer

• Nanopharmaceutical May Offer Benefits in Combinations

A Chimeric RNA Characteristic of Rhabdomyosarcoma in Normal Myogenesis Process . . . . . . . . . . . . . . . . . 1394

H. Yuan, F. Qin, M. Movassagh, H. Park, W. Golden, Z. Xie, P. Zhang, J. Sklar, and H. Li

Précis: A PAX3–FOXO1 chimeric RNA identical to the gene fusion expressed in alveolar rhabdomy-osarcoma is transiently expressed in normal cells during skeletal muscle differentiation.

Discovery of a Mutant-Selective Covalent Inhibitor of EGFR that Overcomes T790M-Mediated Resistance in NSCLC . . . . . . . . . . . . . . . . 1404

A.O. Walter, R. Tjin Than Sjin, H.J. Haringsma, K. Ohashi, J. Sun, K. Lee, A. Dubrovskiy, M. Labenski, Z. Zhu,Z. Wang, M. Sheets, T. St Martin, R. Karp, D. van Kalken, P. Chaturvedi, D. Niu, M. Nacht, R.C. Petter, W. Westlin, K. Lin, S. Jaw-Tsai, M. Raponi, T. Van Dyke, J. Etter, Z. Weaver, W. Pao, J. Singh, A.D. Simmons, T.C. Harding, and A. Allen

Précis: CO-1686 specifi cally and irreversibly inhibits mutant EGFR proteins including EGFRT790M while sparing wild-type EGFR activity.

Individualized Systems Medicine Strategy to Tailor Treatments for Patients with Chemorefractory Acute Myeloid Leukemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1416

T. Pemovska, M. Kontro, B. Yadav, H. Edgren, S. Eldfors, A. Szwajda, H. Almusa, M.M. Bespalov, P. Ellonen, E. Elonen, B.T. Gjertsen, R. Karjalainen, E. Kulesskiy, S. Lagström, A. Lehto, M. Lepistö, T. Lundán, M.M. Majumder, J.M.L. Marti, P. Mattila, A. Murumägi, S. Mustjoki, A. Palva, A. Parsons, T. Pirttinen, M.E. Rämet, M. Suvela, L. Turunen, I. Västrik, M. Wolf, J. Knowles, T. Aittokallio, C.A. Heckman, K. Porkka, O. Kallioniemi, and K. Wennerberg

Précis: Implementation of drug combinations predicted to be effective based on ex vivo drug sensitivity and resistance testing of acute myeloid leukemia samples led to clinical responses.

See commentary, p. 1336

Acknowledgment to Reviewers . . . . . . 1430

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