CANCERDISCOVERY CONTENTS

ii | CANCER DISCOVERY�FEBRUARY 2016 www.aacrjournals.org

FEBRUARY 2016 ≠ VOLUME 6 ≠ NUMBER 2

Mesothelin-Targeted CARs: Driving T Cells to Solid Tumors . . . . . . . . . . . . . . . . . . . 133A. Morello, M. Sadelain, and P.S. Adusumilli

Tumor Heterogeneity and Lesion-Specifi c Response to Targeted Therapy in Colorectal Cancer . . . . . . . . . . . . . . 147M. Russo, G. Siravegna, L.S. Blaszkowsky, G. Corti, G. Crisafulli, L.G. Ahronian, B. Mussolin, E.L. Kwak, M. Buscarino, L. Lazzari, E. Valtorta, M. Truini, N.A. Jessop, H.E. Robinson, T.S. Hong, M. Mino-Kenudson, F. Di Nicolantonio, A. Thabet, A. Sartore-Bianchi, S. Siena, A.J. Iafrate, A. Bardelli, and R.B. CorcoranPrécis: Acquisition of distinct resistance mechanisms in individual metastases within the same patient can result in differential responses to subsequent targeted therapies between lesions.

See commentary, p. 122

Diverse and Targetable Kinase Alterations Drive Histiocytic Neoplasms . . . . . . . . . . . . . . . . . . . . . 154E.L. Diamond, B.H. Durham, J. Haroche, Z. Yao, J. Ma, S.A. Parikh, Z. Wang, J. Choi, E. Kim, F. Cohen-Aubart, S.C.-W. Lee, Y. Gao, J.-B. Micol, P. Campbell, M.P. Walsh, B. Sylvester, I. Dolgalev, O. Aminova, A. Heguy, P. Zappile, J. Nakitandwe, C. Ganzel, J.D. Dalton, D.W. Ellison, J. Estrada-Veras, M. Lacouture, W.A. Gahl, P.J. Stephens, V.A. Miller, J.S. Ross, S.M. Ali, S.R. Briggs, O. Fasan, J. Block, S. Héritier, J. Donadieu, D.B. Solit, D.M. Hyman, J. Baselga, F. Janku, B.S. Taylor, C.Y. Park, Z. Amoura, A. Dogan, J.-F. Emile, N. Rosen, T.A. Gruber, and O. Abdel-WahabPrécis: Recurrent kinase fusion proteins involving BRAF, ALK, and NTRK1 and activating MAP2K1 and ARAF mutations were identifi ed in BRAFV600E–wild-type histiocytic neoplasms, sensitizing cells to kinase inhibitors.

REVIEW

RESEARCHBRIEFS

Highlighted research articles . . . . . . . . . . . . . . . . . . . . . . . . . 109

Important news stories affecting the community . . . . . . . . . . 112

Selected highlights of recent articles of exceptional signifi cance from the cancer literature . . . . . . . . . . . . . . 117

For more News and Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/content/early/by/section.

In The Spotlight

Pruning Cancer’s Evolutionary Tree with Lesion-Directed Therapy . . . . . . . . . . . . . . . . . . . . . . . . 122C.T. Hiley and C. Swanton

See article, p. 147

Adenoid Cystic Carcinoma Can Be Driven by MYB or MYBL1 Rearrangements: New Insights into MYB and Tumor Biology . . . . . . . . . . . . . . . . . 125T.J. Gonda and R.G. Ramsay

See article, p. 176

Immunotherapy and Oncogenic Pathways: The PTEN Connection . . . . . . . . . . . . . . . . . . . . 128N.A. Rizvi and T.A. Chan

See article, p. 202

In Focus

DNA-Guided Precision Medicine for Cancer: A Case of Irrational Exuberance? . . . . . . . . . . . . . . . . . . . 130E.E. Voest and R. Bernards

IN THIS ISSUE

NEWSIN BRIEF

RESEARCH WATCH

ONLINE

VIEWS

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FEBRUARY 2016�CANCER DISCOVERY | iii

Whole Genome Sequencing Defi nes the Genetic Heterogeneity of Familial Pancreatic Cancer . . . . . . . . . . . . . . . . . . . . 166N.J. Roberts, A.L. Norris, G.M. Petersen, M.L. Bondy, R. Brand, S. Gallinger, R.C. Kurtz, S.H. Olson, A.K. Rustgi, A.G. Schwartz, E. Stoffel, S. Syngal, G. Zogopoulos, S.Z. Ali, J. Axilbund, K.G. Chaffee, Y.-C. Chen, M.L. Cote, E.J. Childs, C. Douville, F.S. Goes, J.M. Herman, C. Iacobuzio-Donahue, M. Kramer, A. Makohon-Moore, R.W. McCombie, K.W. McMahon, N. Niknafs, J. Parla, M. Pirooznia, J.B. Potash, A.D. Rhim, A.L. Smith, Y. Wang, C.L. Wolfgang, L.D. Wood, P.P. Zandi, M. Goggins, R. Karchin, J.R. Eshleman, N. Papadopoulos, K.W. Kinzler, B. Vogelstein, R.H. Hruban, and A.P. KleinPrécis: Germline whole-genome sequencing of a large cohort of patients with familial pancreatic cancer identifi ed candidate susceptibility genes and revealed high genetic heterogeneity.

Recurrent Fusions in MYB and MYBL1 Defi ne a Common, Transcription Factor–Driven Oncogenic Pathway in Salivary Gland Adenoid Cystic Carcinoma . . . . . 176K.J. Brayer, C.A. Frerich, H. Kang, and S.A. Ness Précis: RNA-sequencing analysis of adenoid cystic carcinomas detected a recurrent translocation fusing MYB to NFIB as well as translocations fusing MYBL1 to NFIB or RAD51B, and demonstrated that these MYB and MYBL1 fusions are interchangeable oncogenic drivers.

See commentary, p. 125

RESEARCHARTICLES

Stromal Expression of miR-143/145 Promotes Neoangiogenesis in Lung Cancer Development . . . . . . . . . . . . . . . . . 188N. Dimitrova, V. Gocheva, A. Bhutkar, R. Resnick, R.M. Jong, K.M. Miller, J. Bendor, and T. JacksPrécis: Autochthonous mouse models of lung cancer show that normal lung endothelial cell expression of miR-143/145 promotes tumor development by driving neoangiogenesis.

Loss of PTEN Promotes Resistance to T Cell–Mediated Immunotherapy . . . . . . . . . . . . . . . . . . . . . . . 202W. Peng, J.Q. Chen, C. Liu, S. Malu, C. Creasy, M.T. Tetzlaff, C. Xu, J.A. McKenzie, C. Zhang, X. Liang, L.J. Williams, W. Deng, G. Chen, R. Mbofung, A.J. Lazar, C.A. Torres-Cabala, Z.A. Cooper, P.-L. Chen, T.N. Tieu, S. Spranger, X. Yu, C. Bernatchez, M.-A. Forget, C. Haymaker, R. Amaria, J.L. McQuade, I.C. Glitza, T. Cascone, H.S. Li, L.N. Kwong, T.P. Heffernan, J. Hu, R.L. Bassett Jr, M.W. Bosenberg, S.E. Woodman, W.W. Overwijk, G. Lizée, J. Roszik, T.F. Gajewski, J.A. Wargo, J.E. Gershenwald, L. Radvanyi, M.A. Davies, and P. HwuPrécis: PTEN loss reduces T-cell infi ltration and drives immunotherapy resistance in melanoma by increasing immunosuppressive cytokine production and inhibiting autophagy.

See commentary, p. 128

The molecular mechanisms that promote resistance to T cell–mediated immunotherapy in patients with melanoma remain unclear. Peng and col-leagues found that loss of PTEN in melanoma cells suppressed T cell–driven antitumor responses both in vitro and in vivo. Consistent with this finding, PTEN-negative melanomas exhibited impaired infiltration and function of CD8+ T cells and decreased sensitivity to immunotherapy. This immune-suppressive effect was mediated by upregulation of the expression of immunosuppressive cyto-kines and inhibition of autophagy in the absence of PTEN. Selective inhibition of the PI3Kβ isoform restored the sensitivity of PTEN-null melanoma cells to T cell–medi-ated immunotherapy. These results support the notion that loss of PTEN drives re-sistance to immunotherapy in melanoma and suggest that combined treatment with PI3K–AKT inhibitors may enhance the clinical efficacy of immunotherapies. For de-tails, please see the article by Peng and colleagues on page 202.

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2016;6:OF9-216. Cancer Discov     6 (2)

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