CANCER DISCOVERY contents

ii | CANCER DISCOVERY july 2018 www.aacrjournals.org

July 2018 ≠ Volume 8 ≠ Number 7

Efficacy of BGJ398, a Fibroblast Growth Factor Receptor 1–3 Inhibitor, in Patients with Previously Treated Advanced Urothelial Carcinoma with FGFR3 Alterations . . . . . . . 812S .K . Pal, J .E . Rosenberg, J .H . Hoffman-Censits, R . Berger, D .I . Quinn, M .D . Galsky, J . Wolf, C . Dittrich, B . Keam, J .-P . Delord, J .H .M . Schellens, G . Gravis, J . Medioni, P . Maroto, V . Sriuranpong, C . Charoentum, H .A . Burris, V . Grünwald, D . Petrylak, U . Vaishampayan, E . Gez, U . De Giorgi, J .-L . Lee, J . Voortman, S . Gupta, S . Sharma, A . Mortazavi, D .J . Vaughn, R . Isaacs, K . Parker, X . Chen, K . Yu, D . Porter, D . Graus Porta, and D .F . BajorinPrécis: The FGFR1–3 inhibitor BGJ398 achieved responses with an acceptable safety profile in an expansion cohort of 67 patients with metastatic FGFR3-altered urothelial carcinoma .

STK11/LKB1 Mutations and PD-1 Inhibitor Resistance in KRAS-Mutant Lung Adenocarcinoma . . . . . . . . . . . . . . .822F . Skoulidis, M .E . Goldberg, D .M . Greenawalt, M .D . Hellmann, M .M . Awad, J .F . Gainor, A .B . Schrock, R .J . Hartmaier, S .E . Trabucco, L . Gay, S .M . Ali, J .A . Elvin, G . Singal, J .S . Ross, D . Fabrizio, P .M . Szabo, H . Chang, A . Sasson, S . Srinivasan, S . Kirov, J . Szustakowski, P . Vitazka, R . Edwards, J .A . Bufill, N . Sharma, S .-H .I . Ou, N . Peled, D .R . Spigel, H . Rizvi, E .J . Aguilar, B .W . Carter, J . Erasmus, D .F . Halpenny, A .J . Plodkowski, N .M . Long, M . Nishino, W .L . Denning, A . Galan-Cobo, H . Hamdi, T . Hirz, P . Tong, J . Wang, J . Rodriguez-Canales, P .A . Villalobos, E .R . Parra, N . Kalhor, L .M . Sholl, J .L . Sauter, A .A . Jungbluth, M . Mino-Kenudson, R . Azimi, Y .Y . Elamin, J . Zhang, G .C . Leonardi, F . Jiang, K .-K . Wong, J .J . Lee, V .A . Papadimitrakopoulou, I .I . Wistuba, V .A . Miller, G .M . Frampton, J .D . Wolchok, A .T . Shaw, P .A . Jänne, P .J . Stephens, C .M . Rudin, W .J . Geese, L .A . Albacker, and J .V . HeymachPrécis: In patients with KRAS-mutant lung adenocarcinoma, co-occurring alterations in STK11 conferred primary resistance to PD-1 blockade, suggesting that genomic profiling may guide selection of patients likely to respond .

See commentary, p. 794

research articles

Highlighted research articles . . . . . . . . . . . . . . . . . . . . . . . . 781

Important news stories affecting the community . . . . . . . . . 784

The Quest for Off-the-Shelf CAR T Cells . . . . . . . . . . . . . . . . . . . . 787

Selected highlights of recent articles of exceptional significance from the cancer literature . . . . . . . . . . . . . 789

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

in the spotlight

Epistatic Oncogenic Interactions Determine Cancer Susceptibility to Immunotherapy . . . . . . . . . . . . .794I . Etxeberria, A . Teijeira, L .M . Montuenga, P . Berraondo, and I . Melero

See article, p. 822

Stop fRETting the Target: Next-Generation RET Inhibitors Have Arrived . . . . . . . . . . . . . . . . . . 797W .T . Iams and C .M . Lovly

See article, p. 836

Macropinocytosis Fuels Prostate Cancer . . . . . . . . . . . . . . . 800C . Commisso and J . Debnath

See article, p. 866

Prospective

Precision Prevention and Early Detection of Cancer: Fundamental Principles . . . . . . . . . . . . . . . . . . . . . 803T .R . Rebbeck, K . Burns-White, A .T . Chan, K . Emmons, M . Freedman, D .J . Hunter, P . Kraft, F . Laden, L . Mucci, G . Parmigiani, D . Schrag, S . Syngal, R .M . Tamimi, K . Viswanath, M .B . Yurgelun, and J .E . Garber

in this issue

neWs in BrieF

neWs in DePth

research Watch

Online

VieWs

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july 2018 CANCER DISCOVERY | iii

Precision Targeted Therapy with BLU-667 for RET-Driven Cancers . . . . 836V . Subbiah, J .F . Gainor, R . Rahal, J .D . Brubaker, J .L . Kim, M . Maynard, W . Hu, Q . Cao, M .P . Sheets, D . Wilson, K .J . Wilson, L . DiPietro, P . Fleming, M . Palmer, M .I . Hu, L . Wirth, M .S . Brose, S .-H . Ignatius Ou, M . Taylor, E . Garralda, S . Miller, B . Wolf, C . Lengauer, T . Guzi, and E .K . EvansPrécis: BLU-667 is a potent selective RET inhibitor with activity against multiple RET mutations and fusions, and it achieved clinical responses with limited toxicity in four patients with RET-driven tumors .

See commentary, p. 797

NF-κB–Dependent Lymphoid Enhancer Co-option Promotes Renal Carcinoma Metastasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . 850P . Rodrigues, S .A . Patel, L . Harewood, I . Olan, E . Vojtasova, S .E . Syafruddin, M .N . Zaini, E .K . Richardson, J . Burge, A .Y . Warren, G .D . Stewart, K . Saeb-Parsy, S .A . Samarajiwa, and S . VanharantaPrécis: High-throughput enhancer profi ling identifi es metastasis-associated enhancers that are activated to drive CXCR4 expression and metastatic colonization in clear cell renal cell carcinoma .

PTEN Defi ciency and AMPK Activation Promote Nutrient Scavenging and Anabolism in Prostate Cancer Cells . . . . 866S .M . Kim, T .T . Nguyen, A . Ravi, P . Kubiniok, B .T . Finicle,V . Jayashankar, L . Malacrida, J . Hou, J . Robertson,D . Gao, J . Chernoff, M .A . Digman, E .O . Potma, B .J . Tromberg, P . Thibault, and A .L . EdingerPrécis: AMPK-dependent macropinocytosis of necrotic cell debris enhances the growth and survival of PTEN-defi cient prostate cancer cells

See commentary, p. 800

CDK6 Antagonizes p53-Induced Responses during Tumorigenesis . . . . . 884F . Bellutti, A .-S . Tigan, S . Nebenfuehr, M . Dolezal,M . Zojer, R . Grausenburger, S . Hartenberger, S . Kollmann, E . Doma, M . Prchal-Murphy, I .Z . Uras, A . Höllein, D .S . Neuberg, B .L . Ebert, A . Ringler, A .C . Mueller, J .I . Loizou, P .W . Hinds, C . Vogl, G . Heller, S . Kubicek, J . Zuber, M . Malumbres, M . Farlik, A . Villunger, K . Kollmann, and V . SexlPrécis: CDK6 antagonizes p53 to promote leukemia cell growth, and CDK6 loss promotes the outgrowth of p53 mutant malignant cell lines, suggesting a potential risk in therapeutic targeting of CDK6 .

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Skoulidis, Goldberg, Greenawalt, and colleagues linked STK11 mutations to PD-1 inhibitor resistance in KRAS-mutant lung cancer . Patients with lung cancer harboring co-occurring STK11 and KRAS alterations had a lower re-sponse rate to PD-1/PD-L1 blockade than patients with co-occurring KRAS and TP53 alterations or KRAS mutations alone . STK11 alterations were en-riched in PD-L1–negative tumors with an intermediate to high tumor mutation bur-den . However, STK11 alterations were also associated with primary resistance to PD-1 blockade in patients with PD-L1–positive tumors . Stk11 deletion induced de novo resistance to PD-1 inhibition in a mouse model of KRAS-mutant lung adeno-carcinoma . These results demonstrate that STK11 alterations confer primary resis-tance to PD-1/PD-L1 blockade and suggest that genomic profiling may identify patients likely to benefit from PD-1 blockade . For details, please see the article by Skoulidis, Goldberg, Greenawalt, and colleagues on page 822 .

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