Targeting Wnt-driven cancer through the inhibition of Porcupine by LGK974
Jun Liu,Shifeng Pan,Mindy H. Hsieh,Nicholas Ng,Fangxian Sun,Tao Wang,Shailaja Kasibhatla,Alwin Schuller,Allen G. Li,Dai Cheng,Jie Li,Celin Tompkins,Anne Marie Pferdekamper,Auzon Steffy,Jane Cheng,Colleen Kowal,Van Phung,Gui-Rong Guo,Yan Wang,Martin P. Graham,Shannon Flynn,J. Chad Brenner,Chun Li,M. Cristina Villarroel,Peter G. Schultz,Xu Wu,Peter McNamara,William R. Sellers,Lilli Petruzzelli,Anthony Boral,H. Martin Seidel,Margaret E. McLaughlin,Jianwei Che,Thomas E. Carey,Gary J. Vanasse,Jennifer L. Harris +35 more
Reads0
Chats0
TLDR
LGK974 is potent and efficacious in multiple tumor models at well-tolerated doses in vivo, including murine and rat mechanistic breast cancer models driven by MMTV–Wnt1 and a human head and neck squamous cell carcinoma model (HN30).Abstract:
Wnt signaling is one of the key oncogenic pathways in multiple cancers, and targeting this pathway is an attractive therapeutic approach. However, therapeutic success has been limited because of the lack of therapeutic agents for targets in the Wnt pathway and the lack of a defined patient population that would be sensitive to a Wnt inhibitor. We developed a screen for small molecules that block Wnt secretion. This effort led to the discovery of LGK974, a potent and specific small-molecule Porcupine (PORCN) inhibitor. PORCN is a membrane-bound O-acyltransferase that is required for and dedicated to palmitoylation of Wnt ligands, a necessary step in the processing of Wnt ligand secretion. We show that LGK974 potently inhibits Wnt signaling in vitro and in vivo, including reduction of the Wnt-dependent LRP6 phosphorylation and the expression of Wnt target genes, such as AXIN2. LGK974 is potent and efficacious in multiple tumor models at well-tolerated doses in vivo, including murine and rat mechanistic breast cancer models driven by MMTV-Wnt1 and a human head and neck squamous cell carcinoma model (HN30). We also show that head and neck cancer cell lines with loss-of-function mutations in the Notch signaling pathway have a high response rate to LGK974. Together, these findings provide both a strategy and tools for targeting Wnt-driven cancers through the inhibition of PORCN.read more
Citations
More filters
Journal ArticleDOI
Integrative clinical genomics of advanced prostate cancer
Dan R. Robinson,Eliezer M. Van Allen,Eliezer M. Van Allen,Yi-Mi Wu,Nikolaus Schultz,Robert J. Lonigro,Juan Miguel Mosquera,Bruce Montgomery,Mary-Ellen Taplin,Colin C. Pritchard,Gerhardt Attard,Gerhardt Attard,Himisha Beltran,Wassim Abida,Robert K. Bradley,Jake Vinson,Xuhong Cao,Pankaj Vats,Lakshmi P. Kunju,Maha Hussain,Felix Y. Feng,Scott A. Tomlins,Kathleen A. Cooney,David Smith,Christine Brennan,Javed Siddiqui,Rohit Mehra,Yu Chen,Yu Chen,Dana E. Rathkopf,Dana E. Rathkopf,Michael J. Morris,Michael J. Morris,Stephen B. Solomon,Jeremy C. Durack,Victor E. Reuter,Anuradha Gopalan,Jianjiong Gao,Massimo Loda,Rosina T. Lis,Michaela Bowden,Michaela Bowden,Stephen P. Balk,Glenn C. Gaviola,Carrie Sougnez,Manaswi Gupta,Evan Y. Yu,Elahe A. Mostaghel,Heather H. Cheng,Hyojeong Mulcahy,Lawrence D. True,Stephen R. Plymate,Heidi Dvinge,Roberta Ferraldeschi,Roberta Ferraldeschi,Penny Flohr,Penny Flohr,Susana Miranda,Susana Miranda,Zafeiris Zafeiriou,Zafeiris Zafeiriou,Nina Tunariu,Nina Tunariu,Joaquin Mateo,Joaquin Mateo,Raquel Perez-Lopez,Raquel Perez-Lopez,Francesca Demichelis,Francesca Demichelis,Brian D. Robinson,Marc H. Schiffman,David M. Nanus,Scott T. Tagawa,Alexandros Sigaras,Kenneth Eng,Olivier Elemento,Andrea Sboner,Elisabeth I. Heath,Howard I. Scher,Howard I. Scher,Kenneth J. Pienta,Philip W. Kantoff,Johann S. de Bono,Johann S. de Bono,Mark A. Rubin,Peter S. Nelson,Levi A. Garraway,Levi A. Garraway,Charles L. Sawyers,Arul M. Chinnaiyan +89 more
TL;DR: This cohort study provides clinically actionable information that could impact treatment decisions for affected individuals and identified new genomic alterations in PIK3CA/B, R-spondin, BRAF/RAF1, APC, β-catenin, and ZBTB16/PLZF.
Journal ArticleDOI
The multifaceted roles of fatty acid synthesis in cancer
Florian Röhrig,Almut Schulze +1 more
TL;DR: This Review explores how different aspects of FA synthesis promote tumorigenesis and tumour progression and strategies to target this pathway have not yet translated into clinical practice.
Journal ArticleDOI
Can we safely target the WNT pathway
TL;DR: The problems and potential solutions to the vexing situation of aberrant regulation of the WNT pathway are examined and a attempt is made to bring them into perspective.
Journal ArticleDOI
Tackling the cancer stem cells — what challenges do they pose?
TL;DR: The signalling pathways that create cancer stem cells, cell-intrinsic mechanisms that could be exploited for selective elimination or induction of their differentiation, and the role of the tumour microenvironment in sustaining them are discussed.
Journal ArticleDOI
Targeting the Wnt/beta-catenin pathway in cancer: Update on effectors and inhibitors
TL;DR: The Wnt pathway is comprehensively reviewed and its interactions with the Notch and Sonic Hedgehog pathways are presented, including updates on clinical trials in various cancers with inhibitors of Wnt, Notch, and Sonic hedgehog.
References
More filters
Journal ArticleDOI
Wnt/β-catenin signaling and disease.
Hans Clevers,Roel Nusse +1 more
TL;DR: An update of the core Wnt/β-catenin signaling pathway is provided, how its various components contribute to disease, and outstanding questions to be addressed in the future are discussed.
Journal ArticleDOI
The Mutational Landscape of Head and Neck Squamous Cell Carcinoma
Nicolas Stransky,Ann Marie Egloff,Aaron D. Tward,Aaron D. Tward,Aaron D. Tward,Aleksandar Kostic,Aleksandar Kostic,Kristian Cibulskis,Andrey Sivachenko,Gregory Kryukov,Gregory Kryukov,Michael S. Lawrence,Carrie Sougnez,Aaron McKenna,Erica Shefler,Alex H. Ramos,Petar Stojanov,Scott L. Carter,Douglas Voet,Maria L. Cortes,Daniel Auclair,Michael F. Berger,Gordon Saksena,Candace Guiducci,Robert C. Onofrio,Melissa Parkin,Marjorie Romkes,Joel L. Weissfeld,Raja R. Seethala,Lin Wang,Claudia Rangel-Escareño,Juan Carlos Fernández-López,Alfredo Hidalgo-Miranda,Jorge Melendez-Zajgla,Wendy Winckler,Kristin Ardlie,Stacey Gabriel,Matthew Meyerson,Eric S. Lander,Eric S. Lander,Eric S. Lander,Gad Getz,Todd R. Golub,Levi A. Garraway,Jennifer R. Grandis +44 more
TL;DR: In this article, the authors analyzed whole-exome sequencing data from 74 tumor-normal pairs and found that at least 30% of cases harbored mutations in genes that regulate squamous differentiation (for example, NOTCH1, IRF6, and TP63), implicating its dysregulation as a major driver of HNSCC carcinogenesis.
Journal ArticleDOI
Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling
Shih Min A Huang,Yuji Mishina,Shanming Liu,Atwood K. Cheung,Frank Stegmeier,Gregory A. Michaud,Olga Charlat,Elizabeth Wiellette,Yue Zhang,Stephanie Wiessner,Marc Hild,Xiaoying Shi,Christine D. Wilson,Craig Mickanin,Vic E. Myer,Aleem Fazal,Ronald Tomlinson,Fabrizio C. Serluca,Wenlin Shao,Hong Cheng,Michael Shultz,Christina Rau,Markus Schirle,Judith Schlegl,Sonja Ghidelli,Stephen Fawell,Chris Lu,Daniel Curtis,Marc W. Kirschner,Christoph Lengauer,Peter Finan,John A. Tallarico,Tewis Bouwmeester,Jeffery A. Porter,Andreas Bauer,Feng Cong +35 more
TL;DR: This study uses a chemical genetic screen to identify a small molecule, XAV939, which selectively inhibits β-catenin-mediated transcription and reveals new mechanistic insights into the regulation of axin protein homeostasis, which presents new avenues for targeted Wnt pathway therapies.
Journal ArticleDOI
Exome sequencing of head and neck squamous cell carcinoma reveals inactivating mutations in NOTCH1
Nishant Agrawal,Mitchell J. Frederick,Curtis R. Pickering,Chetan Bettegowda,Kyle Chang,Ryan J. Li,Carole Fakhry,Tong Xin Xie,Jiexin Zhang,Jing Wang,Nianxiang Zhang,Adel K. El-Naggar,Samar A. Jasser,John N. Weinstein,Lisa R. Trevino,Jennifer Drummond,Donna M. Muzny,Yuanqing Wu,Laura D. Wood,Ralph H. Hruban,William H. Westra,Wayne M. Koch,Joseph A. Califano,Joseph A. Califano,Richard A. Gibbs,Richard A. Gibbs,David Sidransky,Bert Vogelstein,Victor E. Velculescu,Nickolas Papadopoulos,David A. Wheeler,Kenneth W. Kinzler,Jeffrey N. Myers +32 more
TL;DR: To explore the genetic origins of head and neck squamous cell carcinoma, whole-exome sequencing and gene copy number analyses were used to study 32 primary tumors and identified mutations in FBXW7 and NotCH1, suggesting that NOTCH1 may function as a tumor suppressor gene rather than an oncogene in this tumor type.
Journal ArticleDOI
Small molecule-mediated disruption of Wnt-dependent signaling in tissue regeneration and cancer
Baozhi Chen,Michael E. Dodge,Wei Tang,Jianming Lu,Zhiqiang Ma,Chih Wei Fan,Shuguang Wei,Wayne Hao,Jessica A. Kilgore,Noelle S. Williams,Michael G. Roth,James F. Amatruda,Chuo Chen,Lawrence G. Lum +13 more
TL;DR: Two novel classes of small molecules are discovered that disrupt Wnt pathway responses and contribute to Wnt-independent signal transduction pathways and thus could be broadly exploited for chemical genetics and therapeutic goals.
Related Papers (5)
Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling
Shih Min A Huang,Yuji Mishina,Shanming Liu,Atwood K. Cheung,Frank Stegmeier,Gregory A. Michaud,Olga Charlat,Elizabeth Wiellette,Yue Zhang,Stephanie Wiessner,Marc Hild,Xiaoying Shi,Christine D. Wilson,Craig Mickanin,Vic E. Myer,Aleem Fazal,Ronald Tomlinson,Fabrizio C. Serluca,Wenlin Shao,Hong Cheng,Michael Shultz,Christina Rau,Markus Schirle,Judith Schlegl,Sonja Ghidelli,Stephen Fawell,Chris Lu,Daniel Curtis,Marc W. Kirschner,Christoph Lengauer,Peter Finan,John A. Tallarico,Tewis Bouwmeester,Jeffery A. Porter,Andreas Bauer,Feng Cong +35 more