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CANCER DISCOVERY contents
ii | CANCER DISCOVERY NOVEMBER 2015 www.aacrjournals.org
NOVEmbER 2015 ≠ VOlumE 5 ≠ NumbER 11
Homologous Recombination Deficiency: Exploiting the Fundamental Vulnerability of Ovarian Cancer . . . . . . . . . . . 1137P .A . Konstantinopoulos, R . Ceccaldi, G .I . Shapiro, and A .D . D’Andrea
EGFR Kinase Domain Duplication (EGFR-KDD) Is a Novel Oncogenic Driver in Lung Cancer That Is Clinically Responsive to Afatinib . . . . . . . 1155J .-N . Gallant, J .H . Sheehan, T .M . Shaver, M . Bailey, D . Lipson, R . Chandramohan, M .R . Brewer, S .J . York, M .G . Kris, J .A . Pietenpol, M . Ladanyi, V .A . Miller, S .M . Ali, J . Meiler, and C .M . LovlyPrécis: Clinically observed in-frame tandem duplication of the EGFR kinase domain is a recurrent oncogenic driver alteration in NSCLC and confers sensitivity to EGFR inhibitors .
Genomic Characterization of Brain Metastases Reveals Branched Evolution and Potential Therapeutic Targets . . . .1164P .K . Brastianos, S .L . Carter, S . Santagata, D .P . Cahill, A . Taylor-Weiner, R .T . Jones, E .M . Van Allen, M .S . Lawrence, P .M . Horowitz, K . Cibulskis, K .L . Ligon, J . Tabernero, J . Seoane, E . Martinez-Saez, W .T . Curry, I .F . Dunn, S .H . Paek, S .-H . Park, A . McKenna, A . Chevalier, M . Rosenberg, F .G . Barker II, C .M . Gill, P . Van Hummelen, A .R . Thorner, B .E . Johnson, M .P . Hoang, T .K . Choueiri, S . Signoretti, C . Sougnez, M .S . Rabin, N .U . Lin, E .P . Winer, A . Stemmer-Rachamimov, M . Meyerson, L . Garraway, S . Gabriel, E .S . Lander, R . Beroukhim, T .T . Batchelor, J . Baselga, D .N . Louis, G . Getz, and W .C . HahnPrécis: Sequencing of matched primary tumors and brain metastases reveals branched evolution and frequent oncogenic alterations in potentially targetable pathways .
See commentary, p. 1124
review
research Briefs
Highlighted research articles . . . . . . . . . . . . . . . . . . . . . . . .1111
Important news stories affecting the community . . . . . . . . . . . . . . . . . . . 1114
Shelved 4-1BB Antibodies Make Comeback . . . . . . . . . . . . 1118
Selected highlights of recent articles of exceptional significance from the cancer literature . . . . . . . . . . . . 1119
For more News and Research Watch, visit Cancer Discovery online at http://CDnews .aacrjournals .org .
in The spotlight
Drug-Resistant Brain Metastases: A Role for Pharmacology, Tumor Evolution, and Too-Late Therapy . . . . . . . . 1124T . Stricker and C .L . Arteaga
See article, p. 1164
The SIN1-PH Domain Connects mTORC2 to PI3K . . . . . . . . . . . . . 1127H .-X . Yuan and K .-L . Guan
See article, p. 1194
Large-Scale Drug Screens Support Precision Medicine . . . . . . . . . . 1130J .W . Gray and G .B . Mills
See article, p. 1210.
in focus
All the World’s a Stage: Facilitating Discovery Science and Improved Cancer Care through the Global Alliance for Genomics and Health . . . . . . . . 1133M . Lawler, L .L . Siu, H .L . Rehm, S .J . Chanock, G . Alterovitz, J . Burn, F . Calvo, D . Lacombe, B .T . Teh, K .N . North, and C .L . Sawyers
in This issue
news in Brief
news in DePTh
research waTch
Online
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NOVEMBER 2015 CANCER DISCOVERY | iii
NF2 Loss Promotes Oncogenic RAS-Induced Thyroid Cancers via YAP-Dependent Transactivation of RAS Proteins and Sensitizes Them to MEK Inhibition . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1178M .E .R . Garcia-Rendueles, J .C . Ricarte-Filho, B .R . Untch,I . Landa, J .A . Knauf, F . Voza, V .E . Smith, I . Ganly, B .S . Taylor, Y . Persaud, G . Oler, Y . Fang, S .C . Jhanwar, A . Viale, A . Heguy, K .H . Huberman, F . Giancotti, R . Ghossein, and J .A . FaginPrécis: Loss of NF2 promotes thyroid tumorigenesis by increasing expression of both wild-type and mutant RAS in a YAP-dependent manner, resulting in enhanced dependency on MAPK signaling .
PtdIns(3,4,5)P3-Dependent Activation of the mTORC2 Kinase Complex . . . . . . . . 1194P . Liu, W . Gan, Y .R . Chin, K . Ogura, J . Guo, J . Zhang, B . Wang, J . Blenis, L .C . Cantley, A . Toker, B . Su, and W . WeiPrécis: Association of the SIN1 PH domain with the mTOR kinase domain suppresses mTORC2 kinase activity, which is relieved by PtdIns(3,4,5)P3 binding to SIN1 or by cancer patient–derived SIN1 PH domain mutations that prohibit mTOR binding .
See commentary, p. 1127
research arTicles
Harnessing Connectivity in a Large-Scale Small-Molecule Sensitivity Dataset . . . . . . . . . . . . . . . . . . 1210B . Seashore-Ludlow, M .G . Rees, J .H . Cheah, M . Cokol, E .V . Price, M .E . Coletti, V . Jones, N .E . Bodycombe, C .K . Soule, J . Gould, B . Alexander, A . Li, P . Montgomery, M .J . Wawer, N . Kuru, J .D . Kotz, C .S .-Y . Hon, B . Munoz, T . Liefeld, V . Dančík, J .A . Bittker, M . Palmer, J .E . Bradner, A .F . Shamji, P .A . Clemons, and S .L . SchreiberPrécis: Integration of small-molecule cancer cell line sensitivity profiles with known drug targets and genomic features reveals context-driven vulnerabilities and small-molecule mechanisms of action .
See commentary, p. 1130
Garcia-Rendueles, Ricarte-Filho, and colleagues found that chr22q LOH is a common event in poorly differentiated thyroid cancer (PDTC) and is pref-erentially associated with RAS mutations . In mice, neither thyroid-specific activation of Hras nor Nf2 deletion was sufficient for transformation, but their combined disruption led to highly penetrant PDTC characterized by increased MAPK signaling . Inactivation of the Hippo pathway in NF2-deficient cells increased YAP-mediated transcription of wild-type and mutant RAS isoforms, whereas disruption of YAP–TEAD binding blocked RAS transcription and inhibited cancer cell growth . Additionally, NF2 loss sensitized RAS-mutant thyroid cancer cells to MEK inhibitors . These results identify YAP as a critical effector of RAS-induced tumorigenesis and suggest that inhibition of YAP or MEK may be effective in RAS-driven thyroid cancer . For details, please see the article by Garcia-Rendueles, Ricarte-Filho, and colleagues on page 1178 .
On The cOver
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2015;5:OF14-1223. Cancer Discov 5 (11)
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