ii | CANCER DISCOVERY�MAY 2014 www.aacrjournals.org

CANCERDISCOVERY CONTENTSMAY 2014 ≠ VOLUME 4 ≠ NUMBER 5

Promising SINEs for Embargoing Nuclear–Cytoplasmic Export as an Anticancer Strategy . . . . . .527

D.S.P. Tan, P.L. Bedard, J. Kuruvilla, L.L. Siu, and A.R. Abdul Razak

Effi cacy of Intermittent Combined RAF and MEK Inhibition in a Patient with Concurrent BRAF- and NRAS-Mutant Malignancies . . . .538

O. Abdel-Wahab, V.M. Klimek, A.A. Gaskell, A. Viale, D. Cheng, E. Kim, R. Rampal, M. Bluth, J.J. Harding, M.K. Callahan, T. Merghoub, M.F. Berger, D.B. Solit, N. Rosen, R.L. Levine, and P.B. Chapman

Précis: Intermittent combined use of the

RAF inhibitor vemurafenib and the MEK

inhibitor cobimetinib in a patient with

BRAF-mutant melanoma and NRAS-

mutant leukemia controlled both diseases.

See commentary, p. 510

Activating mTOR Mutations in a Patient with an Extraordinary Response on a Phase I Trial of Everolimus and Pazopanib . . . . . . . 546

N. Wagle, B.C. Grabiner, E.M. Van Allen, E. Hodis, S. Jacobus, J.G. Supko, M. Stewart, T.K. Choueiri, L. Gandhi, J.M. Cleary, A.A. Elfi ky, M.E. Taplin, E.C. Stack, S. Signoretti, M. Loda, G.I. Shapiro, D.M. Sabatini, E.S. Lander, S.B. Gabriel, P.W. Kantoff, L.A. Garraway, and J.E. Rosenberg

Précis: The identifi cation of two activating

MTOR mutations in a patient who experi-

enced a complete response to everolimus

and pazopanib suggests an underlying

mechanism of mTOR inhibitor sensitivity.

See commentary, p. 513

A Diverse Array of Cancer-Associated MTOR Mutations Are Hyperactivating and Can Predict Rapamycin Sensitivity . . . . . . . . . .554

B.C. Grabiner, V. Nardi, K. Birsoy, R. Possemato, K. Shen, S. Sinha, A. Jordan, A.H. Beck, and D.M. Sabatini

Précis: Activating MTOR mutations

are widespread in human cancers and

correlate with hypersensitivity to mTOR

pathway inhibition.

See commentary, p. 513

REVIEW

RESEARCHBRIEFS

Highlighted research articles . . . . . . . . . . . . . . . . . . . . . . . . . 495

Important news stories affecting the community . . . . . . . . . . . . . . . . . . . . . 500

Q&A: Mikala Egeblad on Tumor Microenvironment . . . . . . . . . . . . . 503

Tracking CTCs May Improve Cancer Treatment . . . . . . . . . . . . . 504

Selected highlights of recent articles of exceptional signifi cance from the cancer literature . . . . . . . . . . . . . 505

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

In The Spotlight

Finding the Right Balance of BRAF Inhibition in Melanoma . . . . . . . . 510

M.A. Davies

See article, p. 538

MTOR Mutations in the Crosshairs of Targeted Therapy . . . . . . . . . . . 513

P.A. Rejto and R.T. Abraham

See article, p. 546

See article, p. 554

From Breaking Bad to Worse: Exploiting Homologous DNA Repair Defi ciency in Cancer . . . 516

M.T. Hemann

See article, p. 592

Paths of Resistance to EGFR Inhibitors: Is NF Enough? . . . . . . 519

O. Maertens and K. Cichowski

See article, p. 606

In Focus

T-Cell and NK-Cell Infi ltration into Solid Tumors: A Key Limiting Factor for Effi cacious Cancer Immunotherapy . . . . . . . . . . . . . . . . 522

I. Melero, A. Rouzaut, G.T. Motz, and G. Coukos

IN THIS ISSUE

NEWSIN BRIEF

NEWSIN DEPTH

RESEARCH WATCH

ONLINE

VIEWS

Research. on October 21, 2020. © 2014 American Association for Cancercancerdiscovery.aacrjournals.org Downloaded from

MAY 2014�CANCER DISCOVERY | iii

Vemurafenib treatment was previously shown to uncover an NRAS-mutant

chronic myelomonocytic leukemia (CMML) in a patient with BRAF-mutant

metastatic melanoma. Abdel-Wahab and colleagues report that the com-

bination of vemurafenib and the MEK inhibitor cobimetinib blocked vemu-

rafenib-induced CMML proliferation and restored normal white blood cell

counts in this patient. Intermittent administration of vemurafenib and co-

bimetinib has durably maintained a near-complete melanoma response and has pre-

vented CMML progression in association with decreased levels of CMML-derived

circulating tumor DNA and reduced ERK activation in monocytes. Intermittent com-

bination RAF and MEK inhibitor therapy may thus be useful for treatment of RAS-

driven malignancies arising due to paradoxical activation of wild-type RAF by RAF

inhibitors in RAS-mutant cells. For details, please see the article by Abdel-Wahab

and colleagues on page 538.

ON THE COVER

NUP98–PHF23 Is a Chromatin-Modifying Oncoprotein That Causes a Wide Array of Leukemias Sensitive to Inhibition of PHD Histone Reader Function . . . . . . . . . . . . . . . . . 564

S.M. Gough, F. Lee, F. Yang, R.L. Walker, Y.J. Zhu, M. Pineda, M. Onozawa, Y.J. Chung, S. Bilke, E.K. Wagner, J.M. Denu, Y. Ning, B. Xu, G.G. Wang, P.S. Meltzer, and P.D. Aplan

Précis: The NUP98–PHF23 fusion induces

hematologic malignancies marked by Hoxa and

Meis1 overexpression and confers sensitivity to

small molecules that block PHD domain binding to

H3K4me3.

A Small-Molecule c-Rel Inhibitor Reduces Alloactivation of T Cells without Compromising Antitumor Activity . . . . . .578

Y. Shono, A.Z. Tuckett, S. Ouk, H.-C. Liou, G. Altan-Bonnet, J.J. Tsai, J.E. Oyler, O.M. Smith, M.L. West, N.V. Singer, E. Doubrovina, D. Pankov, C.V. Undhad, G.F. Murphy, C. Lezcano, C. Liu, R.J. O’Reilly, M.R.M. van den Brink, and J.L. Zakrzewski

Précis: c-Rel is required for T-cell activation in

grant-versus-host disease but is dispensable for

graft-versus-tumor activity.

RESEARCHARTICLES

A Functional Cancer Genomics Screen Identifi es a Druggable Synthetic Lethal Interaction between MSH3 and PRKDC . . . . . . . . . . . . . . . . . . . . 592

F. Dietlein, L. Thelen, M. Jokic, R.D. Jachimowicz,L. Ivan, G. Knittel, U. Leeser, J. van Oers, W. Edelmann, L.C. Heukamp, and H.C. Reinhardt

Précis: A DNA-PKcs inhibitor sensitivity screen of

genomically annotated cancer cell lines identifi es

MSH3 mutations as predictive of DNA-PKcs

nononcogene addiction.

See commentary, p. 516

Reduced NF1 Expression Confers Resistance to EGFR Inhibition in Lung Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 606

E.C. de Bruin, C. Cowell, P.H. Warne, M. Jiang,R.E. Saunders, M.A. Melnick, S. Gettinger, Z. Walther, A. Wurtz, G.J. Heynen, D.A.M. Heideman,J. Gómez-Román, A. García-Castaño, Y. Gong, M. Ladanyi, H. Varmus, R. Bernards, E.F. Smit, K. Politi, and J. Downward

Précis: NF1 defi ciency sustains MAPK pathway

activation and reduces sensitivity to EGFR kinase

inhibitors in the absence of the EGFRT790M mutation.

See commentary, p. 519

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