CANCER DISCOVERY CONTENTScancerdiscovery.aacrjournals.org/.../candisc/6/10.toc.pdfCANCER DISCOVERY...
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CANCER DISCOVERY CONTENTS ii | CANCER DISCOVERYOCTOBER 2016 www.aacrjournals.org OCTOBER 2016 ≠ VOLUME 6 ≠ NUMBER 10 Efficacy and Biological Correlates of Response in a Phase II Study of Venetoclax Monotherapy in Patients with Acute Myelogenous Leukemia . . . . . . . . . . . . . . . . . . . . . 1106 M. Konopleva, D.A. Pollyea, J. Potluri, B. Chyla, L. Hogdal, T. Busman, E. McKeegan, A.H. Salem, M. Zhu, J.L. Ricker, W. Blum, C.D. DiNardo, T. Kadia, M. Dunbar, R. Kirby, N. Falotico, J. Leverson, R. Humerickhouse, M. Mabry, R. Stone, H. Kantarjian, and A. Letai Précis: Venetoclax monotherapy has clinical activity and is generally well tolerated in patients with heavily pretreated AML, and BCL2 dependence and lack of BCL-X L and MCL1 dependence predicted the best response. See commentary, p. 1082 Molecular Mechanisms of Resistance to First- and Second-Generation ALK Inhibitors in ALK-Rearranged Lung Cancer . . . . . . . . . . . . . . . . . . 1118 J.F. Gainor, L. Dardaei, S. Yoda, L. Friboulet, I. Leshchiner, R. Katayama, I. Dagogo-Jack, S. Gadgeel, K. Schultz, M. Singh, E. Chin, M. Parks, D. Lee, R.H. DiCecca, E. Lockerman, T. Huynh, J. Logan, L.L. Ritterhouse, L.P. Le, A. Muniappan, S. Digumarthy, C. Channick, C. Keyes, G. Getz, D. Dias-Santagata, R.S. Heist, J. Lennerz, L.V. Sequist, C.H. Benes, A.J. Iafrate, M. Mino-Kenudson, J.A. Engelman, and A.T. Shaw Précis: Molecular mechanisms of resistance to ALK inhibitors were characterized in ALK-positive lung cancer. See commentary, p. 1084 Systematic Functional Characterization of Resistance to PI3K Inhibition in Breast Cancer . . . . . . . . . . . . . . . . . . . . . . . . 1134 X. Le, R. Antony, P. Razavi, D.J. Treacy, F. Luo, M. Ghandi, P. Castel, M. Scaltriti, J. Baselga, and L.A. Garraway Précis: PIM kinases promote resistance to PI3K inhibition in PIK3CA-mutant breast cancer by activating downstream PI3K effectors in an AKT-independent manner. RESEARCH ARTICLES Highlighted research articles . . . . . . . . . . . . . . . . . . . . . . . .1069 Important news stories affecting the community . . . . . . . . 1072 Q&A: Gordon Mills on Neomorphs in Cancer . . . . . . . . . 1076 Selected highlights of recent articles of exceptional significance from the cancer literature . . . . . . . . . . . . 1077 For more News and Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/ content/early/by/section. In The Spotlight BCL2 Inhibition by Venetoclax: Targeting the Achilles’ Heel of the Acute Myeloid Leukemia Stem Cell? . . . . . . . . . . . . . . . . . . . 1082 V.A. Pullarkat and E.M. Newman See article, p. 1106 Cracking the Code of Resistance across Multiple Lines of ALK Inhibitor Therapy in Lung Cancer . . . . . . . . . . . . . . . . . . . . . . . 1084 H. Qiao and C.M. Lovly See article, p. 1118 Accurate Medicine: Indirect Targeting of NPM1-Mutated AML . . . . . . . . 1087 C.S. Hourigan and P.D. Aplan See article, p. 1166 Targeting PI3K in Cancer: Impact on Tumor Cells, Their Protective Stroma, Angiogenesis, and Immunotherapy . . . . . . . . . . . . . . 1090 K. Okkenhaug, M. Graupera, and B. Vanhaesebroeck IN THIS ISSUE NEWS IN BRIEF NEWS IN DEPTH RESEARCH WATCH ONLINE VIEWS REVIEW Research. on February 27, 2019. © 2016 American Association for Cancer cancerdiscovery.aacrjournals.org Downloaded from
Transcript of CANCER DISCOVERY CONTENTScancerdiscovery.aacrjournals.org/.../candisc/6/10.toc.pdfCANCER DISCOVERY...
CANCERDISCOVERY CONTENTS
ii | CANCER DISCOVERY�OCTOBER 2016 www.aacrjournals.org
OCTOBER 2016 ≠ VOLUME 6 ≠ NUMBER 10
Effi cacy and Biological Correlates of Response in a Phase II Study of Venetoclax Monotherapy in Patients with Acute Myelogenous Leukemia . . . . . . . . . . . . . . . . . . . . . 1106M. Konopleva, D.A. Pollyea, J. Potluri, B. Chyla, L. Hogdal, T. Busman, E. McKeegan, A.H. Salem, M. Zhu, J.L. Ricker, W. Blum, C.D. DiNardo, T. Kadia, M. Dunbar, R. Kirby, N. Falotico, J. Leverson, R. Humerickhouse, M. Mabry, R. Stone, H. Kantarjian, and A. LetaiPrécis: Venetoclax monotherapy has clinical activity and is generally well tolerated in patients with heavily pretreated AML, and BCL2 dependence and lack of BCL-XL and MCL1 dependence predicted the best response.
See commentary, p. 1082
Molecular Mechanisms of Resistance to First- and Second-Generation ALK Inhibitors in ALK-Rearranged Lung Cancer . . . . . . . . . . . . . . . . . . 1118J.F. Gainor, L. Dardaei, S. Yoda, L. Friboulet, I. Leshchiner, R. Katayama, I. Dagogo-Jack,S. Gadgeel, K. Schultz, M. Singh, E. Chin, M. Parks, D. Lee, R.H. DiCecca, E. Lockerman, T. Huynh, J. Logan, L.L. Ritterhouse, L.P. Le,A. Muniappan, S. Digumarthy, C. Channick, C. Keyes, G. Getz, D. Dias-Santagata, R.S. Heist, J. Lennerz, L.V. Sequist, C.H. Benes, A.J. Iafrate, M. Mino-Kenudson, J.A. Engelman, and A.T. ShawPrécis: Molecular mechanisms of resistance to ALK inhibitors were characterized in ALK-positive lung cancer.
See commentary, p. 1084
Systematic Functional Characterization of Resistance to PI3K Inhibition in Breast Cancer . . . . . . . . . . . . . . . . . . . . . . . . 1134X. Le, R. Antony, P. Razavi, D.J. Treacy, F. Luo, M. Ghandi, P. Castel, M. Scaltriti, J. Baselga, and L.A. GarrawayPrécis: PIM kinases promote resistance to PI3K inhibition in PIK3CA-mutant breast cancer by activating downstream PI3K effectors in an AKT-independent manner.
RESEARCHARTICLES
Highlighted research articles . . . . . . . . . . . . . . . . . . . . . . . .1069
Important news stories affecting the community . . . . . . . . 1072
Q&A: Gordon Mills on Neomorphs in Cancer . . . . . . . . .1076
Selected highlights of recent articles of exceptional signifi cance from the cancer literature . . . . . . . . . . . . 1077
For more News and Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/content/early/by/section.
In The Spotlight
BCL2 Inhibition by Venetoclax: Targeting the Achilles’ Heel of the Acute Myeloid Leukemia Stem Cell? . . . . . . . . . . . . . . . . . . . 1082V.A. Pullarkat and E.M. Newman
See article, p. 1106
Cracking the Code of Resistance across Multiple Lines of ALK Inhibitor Therapy in Lung Cancer . . . . . . . . . . . . . . . . . . . . . . . 1084H. Qiao and C.M. Lovly
See article, p. 1118
Accurate Medicine: Indirect Targeting of NPM1-Mutated AML . . . . . . . .1087C.S. Hourigan and P.D. Aplan
See article, p. 1166
Targeting PI3K in Cancer: Impact on Tumor Cells, Their Protective Stroma, Angiogenesis, and Immunotherapy . . . . . . . . . . . . . . 1090K. Okkenhaug, M. Graupera, and B. Vanhaesebroeck
IN THIS ISSUE
NEWSIN BRIEF
NEWSIN DEPTH
RESEARCH WATCH
ONLINE
VIEWS
REVIEW
Research. on February 27, 2019. © 2016 American Association for Cancercancerdiscovery.aacrjournals.org Downloaded from
OCTOBER 2016�CANCER DISCOVERY | iii
Integrin-α10 Dependency Identifi es RAC and RICTOR as Therapeutic Targets in High-Grade Myxofi brosarcoma . . . . . . 1148T. Okada, A.Y. Lee, L.-X. Qin, N. Agaram, T. Mimae, Y. Shen, R. O’Connor, M.A. López-Lago, A. Craig, M.L. Miller, P. Agius, E. Molinelli, N.D. Socci, A.M. Crago, F. Shima, C. Sander, and S. SingerPrécis: Integrin-α10 drives high-grade myxofi brosarcoma growth and survival by interacting with TRIO and RICTOR, which are commonly overexpressed in this disease, to activate RAC and AKT signaling.
Targeting Chromatin Regulators Inhibits Leukemogenic Gene Expression in NPM1 Mutant Leukemia . . . . . . . . . . . . . . . . . . . . 1166M.W.M. Kühn, E. Song, Z. Feng, A. Sinha, C.-W. Chen, A.J. Deshpande, M. Cusan, N. Farnoud, A. Mupo, C. Grove, R. Koche, J.E. Bradner, E. de Stanchina, G.S. Vassiliou, T. Hoshii, and S.A. ArmstrongPrécis: MLL1 and DOT1L regulate expression of HOX, MEIS1, and FLT3 to suppress differentiation and promote NPM1-mutant leukemogenesis and are potential therapeutic targets.
See commentary, p. 1087
Polarization of Tissue-Resident TFH-Like Cells in Human Hepatoma Bridges Innate Monocyte Infl ammation and M2b Macrophage Polarization . . 1182M.-M. Chen, X. Xiao, X.-M. Lao, Y. Wei, R.-X. Liu, Q.-H. Zeng, J.-C. Wang, F.-Z. Ouyang, D.-P. Chen, K.-W. Chan, D.-C. Shi, L. Zheng, and D.-M. KuangPrécis: Infl ammatory monocytes in the tumor microenvironment induce a subset of IFNγ-producing IL21+ T helper cells that promote B-cell maturation, which subsequently stimulates protumorigenic macrophage polarization.
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Gainor, Dardaei, and colleagues performed a molecular and functional analysis of repeat biopsies from patients with ALK-rearranged non–small cell lung cancer who developed ALK inhibitor resistance. ALK resistance mutations were more common after treatment with second-generation ALK inhibitors com-pared to treatment with the first-generation ALK inhibitor crizotinib, and each ALK inhibitor exhibited a specific spectrum of ALK resistance mutations. Identification of epithelial–mesenchymal transition (EMT) in a subset of second-generation ALK inhibitor–resistant biopsies suggested that EMT may contribute to second-generation ALK inhibitor resistance. The third-generation ALK inhibitor lorlati-nib exhibited potency against single and compound ALK resistance mutations induced by second-generation ALK inhibitors. Together, these results describe the molecular mechanisms of resistance to first- and second-generation ALK inhibitors and highlight the importance of longitudinal sampling. For details, please see the article by Gainor, Dardaei, and colleagues on page 1118.
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