CANCER DISCOVERY CONTENTS · CANCER DISCOVERYMAY 2014 | iii Vemurafenib treatment was previously shown to uncover an NRAS-mutant chronic myelomonocytic leukemia (CMML) in a patient
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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
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
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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