ii | CANCER DISCOVERY�FEBRUARY 2013 www.aacrjournals.org

CANCERDISCOVERY CONTENTSFEBRUARY 2013 ≠ VOLUME 3 ≠ NUMBER 2

From Differences in Means between Cases and Controls to Risk Stratifi cation: A Business Plan for Biomarker Development . . . . . . . . . . . . . . . . . 148N. Wentzensen and S. Wacholder

Inhibiting EGF Receptor or SRC Family Kinase Signaling Overcomes BRAF Inhibitor Resistance in Melanoma . . . . . . .158M.R. Girotti, M. Pedersen, B. Sanchez-Laorden, A. Viros, S. Turajlic,D. Niculescu-Duvaz, A. Zambon, J. Sinclair,A. Hayes, M. Gore, P. Lorigan, C. Springer, J. Larkin, C. Jorgensen, and R. MaraisPrécis: Activation of an EGFR–SRC family kinase signaling axis contributes to intrinsic and acquired vemurafenib resistance in BRAF-mutant melanoma.

Noncovalent Wild-type–Sparing Inhibitors of EGFR T790M . . . . .168H.-J. Lee, G. Schaefer, T.P. Heffron, L. Shao, X. Ye, S. Sideris, S. Malek, E. Chan, M. Merchant, H. La, S. Ubhayakar, R.L. Yauch, V. Pirazzoli, K. Politi, and J. SettlemanPrécis: Clinically available indolocarbazole analogues reversibly inhibit the EGFR T790M mutant without affecting wild-type EGFR.

See commentary, p. 138

Senescence Sensitivity of Breast Cancer Cells Is Defi ned by Positive Feedback Loop between CIP2A and E2F1 . . . . . . . . . . . . . . . . . . . . . .182A. Laine, H. Sihto, C. Come, M.T. Rosenfeldt, A. Zwolinska, M. Niemelä, A. Khanna, E.K. Chan, V.-M. Kähäri, P.-L. Kellokumpu-Lehtinen, O.J. Sansom, G.I. Evan, M.R. Junttila, K.M. Ryan, J.-C. Marine, H. Joensuu, and J. WestermarckPrécis: An E2F1–CIP2A feedback loop downstream of p53 or p21 inactivation prevents senescence induction in breast cancer cells and contributes to chemotherapeutic resistance.

REVIEW

RESEARCHBRIEF

RESEARCHARTICLES

Highlighted research articles . . . . . . . . . . . . . . . . . . . . . . . . . . . 125

Important news stories affecting the community . . . . . . . . . . . . . . . . . . . . 128

Q&A: John Dick on Stem Cells and Cancer . . . . . . . . . . . . . . . . . . . . 131

Taking Cancer-Drug Toxicity to Heart . . . . . . . . . . . . . . . . . . . . . . . 132

Selected highlights of recent articles of exceptional signifi cance from the cancer literature . . . . . . . . . . . . . 133

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

In The Spotlight

Maximizing the Benefi ts of Off-Target Kinase Inhibitor Activity . . . . . . . . . . . . . . . . . . . . . . . .138M.R. Brewer and W. Pao

See article, p. 168

Mitotic Control of Cancer Stem Cells . . . . . . . . . . . . . . . . . . . . .141M. Venere, T.E. Miller, and J.N. Rich

See article, p. 198

Activating Mutations in HER2: Neu Opportunities and Neu Challenges . . . . . . . . . . . . . . . . . . . . .145B. Weigelt and J.S. Reis-Filho

See article, p. 224

IN THIS ISSUE

NEWSIN BRIEF

NEWSIN DEPTH

RESEARCH WATCH

ONLINE

VIEWS

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FEBRUARY 2013�CANCER DISCOVERY | iii

Cancer-Specifi c Requirement for BUB1B/BUBR1 in Human Brain Tumor Isolates and Genetically Transformed Cells . . . . . . . . . . . . . . . . . . . . 198Y. Ding, C.G. Hubert, J. Herman, P. Corrin, C.M. Toledo, K. Skutt-Kakaria, J. Vazquez, R. Basom, B. Zhang, J.K. Risler, S.M. Pollard, D.-H. Nam, J.J. Delrow, J. Zhu, J. Lee, J. DeLuca, J.M. Olson, and P.J. PaddisonPrécis: Oncogenic transformation can induce short interkinetochore distances and confer dependence on the mitotic protein BUB1B.

See commentary, p. 141

Antagonism of Inhibitor of Apoptosis Proteins Increases Bone Metastasis via Unexpected Osteoclast Activation . . . . . 212C. Yang, J.L. Davis, R. Zeng, P. Vora, X. Su, L.I. Collins, S. Vangveravong, R.H. Mach, D. Piwnica-Worms, K.N. Weilbaecher, R. Faccio, and D.V. NovackPrécis: IAP antagonists induce alternative NF-κB signaling and osteoclast activity to promote bone metastasis, thus limiting their effi cacy as antitumor agents.

Activating HER2 Mutations in HER2 Gene Amplifi cation Negative Breast Cancer . . . . . . . . . . . . . . . . . . . . . . . . 224R. Bose, S.M. Kavuri, A.C. Searleman, W. Shen, D. Shen, D.C. Koboldt, J. Monsey, N. Goel, A.B. Aronson, S. Li, C.X. Ma, L. Ding, E.R. Mardis, and M.J. EllisPréc is: Gain-of-function HER2 mutations were identifi ed in breast cancers lacking HER2 gene amplifi cation and retained sensitivity to the irreversible kinase inhibitor neratinib.

See commentary, p. 145

Bose and colleagues functionally characterized 13 somatic HER2 muta-tions identified by genome sequencing in breast cancers lacking HER2 gene amplification. Protein structure analysis showed that these muta-tions largely clustered in either the HER2 tyrosine kinase or extra-cellular domain. Many of these were gain-of-function mutations that enhanced HER2 kinase activity and downstream signaling, promoted anchorage-independent growth, and accelerated tumor formation, suggesting that HER2 mutations may be driver events in breast cancer. Although several mutations conferred resistance to lapatinib, all mutations were sensitive to the irreversible HER2 kinase inhibitor neratinib. These findings suggest that patients with HER2 mutation–positive breast cancer may benefit from HER2-targeted therapies. For details, please see the article by Bose and colleagues on page 224.

ON THE COVER

For more News and Research Watch, visit Cancer Discovery online at http://CDnews.aacrjournals.org. Online-only News stories include the following:

• Ibrutinib Impresses in Early Trials• NCAB Gains New Members• EMA Boosts Transparency for Trials

• Cancer Screening Participation Shows Some Dips• Proton Therapy Appears to Be Less Cost-Effective• Study Reveals Global Shifts in Causes of Death

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