Journal ArticleDOI
PI3K inhibitors are finally coming of age.
TLDR
In this paper, Vanhaesebroeck et al. review efforts to understand and therapeutically exploit the biology of PI3Kα and PI3kδ pathway inhibitors, highlighting lessons learned and future opportunities.Abstract:
Overactive phosphoinositide 3-kinase (PI3K) in cancer and immune dysregulation has spurred extensive efforts to develop therapeutic PI3K inhibitors. Although progress has been hampered by issues such as poor drug tolerance and drug resistance, several PI3K inhibitors have now received regulatory approval — the PI3Kα isoform-selective inhibitor alpelisib for the treatment of breast cancer and inhibitors mainly aimed at the leukocyte-enriched PI3Kδ in B cell malignancies. In addition to targeting cancer cell-intrinsic PI3K activity, emerging evidence highlights the potential of PI3K inhibitors in cancer immunotherapy. This Review summarizes key discoveries that aid the clinical translation of PI3Kα and PI3Kδ inhibitors, highlighting lessons learnt and future opportunities PI3K signalling is one of the most frequently aberrantly activated pathways in cancer. However, the development of therapeutic PI3K pathway inhibitors has faced challenges including poor drug tolerance and drug resistance. Here, Vanhaesebroeck et al. review efforts to understand and therapeutically exploit the biology of PI3Kα and PI3Kδ — the key targets of currently approved PI3K inhibitors, highlighting lessons learned and future opportunities.read more
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PI3K/Akt/mTOR Pathway and Its Role in Cancer Therapeutics: Are We Making Headway?
TL;DR: Overall, an in-depth understanding of the association between the PI3K/AKT/mTOR pathway and tumorigenesis and the development of therapies targeting the PI 3K/ AKT/ mTOR pathway will help make clinical decisions.
Journal ArticleDOI
Phosphoinositides as membrane organizers
TL;DR: A review of the current understanding of how phosphoinositides shape and direct membrane dynamics to impact on cell physiology, and an overview of emerging concepts in PHO regulation can be found in this article .
Journal ArticleDOI
Targeting PI3K/AKT/mTOR Signaling Pathway in Breast Cancer.
TL;DR: In this article, the authors provide a perspective on the role of the PI3K signaling pathway and the most recently developed PI3k-targeting breast cancer therapies, and provide an overview of the most commonly altered pathways driving breast cancer cell growth, survival, and motility.
Journal ArticleDOI
Targeting oncogene and non-oncogene addiction to inflame the tumour microenvironment
TL;DR: Both oncogene and non-oncogene addiction stand out as promising targets to robustly inflame the TME and potentially enable superior responses to ICIs.
Journal ArticleDOI
At a crossroads: how to translate the roles of PI3K in oncogenic and metabolic signalling into improvements in cancer therapy
Neil Vasan,Lewis C. Cantley +1 more
TL;DR: This Review discusses past and present efforts to overcome the somewhat limited clinical efficacy of PI3Kα pathway inhibitors, including optimization of inhibitor specificity, patient selection and biomarkers across cancer types, with a focus on breast cancer, and interventions to improve management of prohibitive adverse events.
References
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TL;DR: The interim integrative analysis of DNA copy number, gene expression and DNA methylation aberrations in 206 glioblastomas reveals a link between MGMT promoter methylation and a hypermutator phenotype consequent to mismatch repair deficiency in treated gliobeasts, demonstrating that it can rapidly expand knowledge of the molecular basis of cancer.
Journal ArticleDOI
Comprehensive molecular characterization of gastric adenocarcinoma
Adam J. Bass,Vesteinn Thorsson,Ilya Shmulevich,Sheila Reynolds,Michael Miller,Brady Bernard,Toshinori Hinoue,Peter W. Laird,Christina Curtis,Hui Shen,Daniel J. Weisenberger,Nikolaus Schultz,Ronglai Shen,Nils Weinhold,David P. Kelsen,Reanne Bowlby,Andy Chu,Katayoon Kasaian,Andrew J. Mungall,A. Gordon Robertson,Payal Sipahimalani,Andrew D. Cherniack,Gad Getz,Yingchun Liu,Michael S. Noble,Chandra Pedamallu,Carrie Sougnez,Amaro Taylor-Weiner,Rehan Akbani,Ju Seog Lee,Wenbin Liu,GB Mills,Da Yang,Wei Zhang,Angeliki Pantazi,Michael Parfenov,Margaret L. Gulley,M. Blanca Piazuelo,Barbara G. Schneider,Jihun Kim,Alex Boussioutas,Margi Sheth,John A. Demchok,Charles S. Rabkin,Joseph Willis,Sam Ng,Katherine S. Garman,David G. Beer,Arjun Pennathur,Benjamin J. Raphael,Hsin-Ta Wu,Robert D. Odze,Hark Kyun Kim,Jay Bowen,Kristen M. Leraas,Tara M. Lichtenberg,Stephanie Weaver,Michael D. McLellan,Maciej Wiznerowicz,Ryo Sakai,Michael S. Lawrence,Kristian Cibulskis,Lee Lichtenstein,Sheila Fisher,Stacey Gabriel,Eric S. Lander,Li Ding,Beifang Niu,Adrian Ally,Miruna Balasundaram,Inanc Birol,Denise Brooks,Yaron S.N. Butterfield,Rebecca Carlsen,Justin Chu,Eric Chuah,Hye Jung E. Chun,Amanda Clarke,Noreen Dhalla,Ranabir Guin,Robert A. Holt,Steven J.M. Jones,Darlene Lee,Haiyan A. Li,Emilia L. Lim,Yussanne Ma,Marco A. Marra,Michael Mayo,Richard A. Moore,Karen Mungall,Ka Ming Nip,Jacqueline E. Schein,Angela Tam,Nina Thiessen,Rameen Beroukhim,Scott L. Carter,Andrew D. Cherniack,Juok Cho,Daniel DiCara,Scott Frazer,Nils Gehlenborg,David I. Heiman,Joonil Jung,Jaegil Kim,Pei Lin,Matthew Meyerson,Akinyemi I. Ojesina,Chandra Sekhar Pedamallu,Gordon Saksena,Steven E. Schumacher,Petar Stojanov,Barbara Tabak,Doug Voet,Mara Rosenberg,Travis I. Zack,Hailei Zhang,Lihua Zou,Alexei Protopopov,Netty Santoso,Semin Lee,Jianhua Zhang,Harshad S. Mahadeshwar,Jiabin Tang,Xiaojia Ren,Sahil Seth,Lixing Yang,Andrew Wei Xu,Xingzhi Song,Ruibin Xi,Christopher A. Bristow,Angela Hadjipanayis,Jonathan G. Seidman,Lynda Chin,Peter J. Park,Raju Kucherlapati,Shiyun Ling,Arvind Rao,John N. Weinstein,Sang Bae Kim,Yiling Lu,Gordon B. Mills,Moiz S. Bootwalla,Phillip H. Lai,Timothy J. Triche,David Van Den Berg,Stephen B. Baylin,James G. Herman,Bradley A. Murray,B. Arman Askoy,Giovanni Ciriello,Gideon Dresdner,Jianjiong Gao,Benjamin Gross,Anders Jacobsen,William Lee,Ricardo Ramirez,Chris Sander,Yasin Senbabaoglu,Rileen Sinha,S. Onur Sumer,Yichao Sun,Lisa Iype,Roger Kramer,Richard Kreisberg,Hector Rovira,Natalie Tasman,Santa Cruz Sam Ng,David Haussler,Josh Stuart,Roeland Verhaak,Mark D.M. Leiserson,Barry S. Taylor,Aaron D. Black,Julie Ann Carney,Julie M. Gastier-Foster,Carmen Helsel,Cynthia McAllister,Nilsa C. Ramirez,Teresa R. Tabler,Lisa Wise,Erik Zmuda,Robert Penny,Daniel Crain,Johanna Gardner,Kevin Lau,Erin Curely,David Mallery,Scott Morris,Joseph Paulauskis,Troy Shelton,Candace Shelton,Mark E. Sherman,Christopher C. Benz,Jae Hyuk Lee,Konstantin V. Fedosenko,Georgy Manikhas,Olga Potapova,Olga Voronina,Smitry Belyaev,Oleg Dolzhansky,W. Kimryn Rathmell,Jakub Brzezinski,Matthew Ibbs,Konstanty Korski,Witold Kycler,Radoslaw ŁaŸniak,Ewa Leporowska,Andrzej Mackiewicz,Dawid Murawa,Pawel Murawa,Arkadiusz Spychała,Wiktoria Maria Suchorska,Honorata Tatka,M. Teresiak,Raafat Abdel-Misih,Joseph J. Bennett,Jennifer Brown,Mary Iacocca,Brenda Rabeno,Sun Young Kwon,Ariane Kemkes,Erin Curley,Iakovina Alexopoulou,Jay Engel,John M. S. Bartlett,Monique Albert,Do-Youn Park,Rajiv Dhir,James D. Luketich,Rodney J. Landreneau,Yelena Y. Janjigian,Eunjung Cho,Marc Ladanyi,Laura H. Tang,Shannon J. McCall,Young Soo Park,Jae Ho Cheong,Jaffer A. Ajani,M. Constanza Camargo,Shelley Alonso,Brenda Ayala,Mark A. Jensen,Todd Pihl,Rohini Raman,Jessica Walton,Yunhu Wan,Greg Eley,Kenna R. Mills Shaw,Roy Tarnuzzer,Zhining Wang,Liming Yang,Jean C. Zenklusen,Tanja M. Davidsen,Carolyn M. Hutter,Heidi J. Sofia,Robert Burton,Sudha Chudamani,Jia Liu +257 more
TL;DR: A comprehensive molecular evaluation of 295 primary gastric adenocarcinomas as part of The Cancer Genome Atlas (TCGA) project is described and a molecular classification dividing gastric cancer into four subtypes is proposed.
Journal ArticleDOI
Comprehensive genomic characterization of head and neck squamous cell carcinomas
Michael S. Lawrence,Carrie Sougnez,Lee Lichtenstein,Kristian Cibulskis,Eric S. Lander,Stacey Gabriel,Gad Getz,Adrian Ally,Miruna Balasundaram,Inanc Birol,Reanne Bowlby,Denise Brooks,Yaron S.N. Butterfield,Rebecca Carlsen,Dean Cheng,Andy Chu,Noreen Dhalla,Ranabir Guin,Robert A. Holt,Steven J.M. Jones,Darlene Lee,Haiyan I. Li,Marco A. Marra,Michael Mayo,Richard A. Moore,Andrew J. Mungall,A. Gordon Robertson,Jacqueline E. Schein,Payal Sipahimalani,Angela Tam,Nina Thiessen,Tina Wong,Alexei Protopopov,Netty Santoso,Semin Lee,Michael Parfenov,Jianhua Zhang,Harshad S. Mahadeshwar,Jiabin Tang,Xiaojia Ren,Sahil Seth,Psalm Haseley,Dong Zeng,Lixing Yang,Andrew Wei Xu,Xingzhi Song,Angeliki Pantazi,Christopher A. Bristow,Angela Hadjipanayis,Jonathan G. Seidman,Lynda Chin,Peter J. Park,Raju Kucherlapati,Rehan Akbani,Tod D. Casasent,Wenbin Liu,Yiling Lu,Gordon B. Mills,Thomas C. Motter,John N. Weinstein,Lixia Diao,Jing Wang,You Hong Fan,Jinze Liu,Kai Wang,J. Todd Auman,Saianand Balu,Thomas Bodenheimer,Elizabeth Buda,D. Neil Hayes,Katherine A. Hoadley,Alan P. Hoyle,Stuart R. Jefferys,Corbin D. Jones,Patrick K. Kimes,Yufeng Liu,James Stephen Marron,Shaowu Meng,Piotr A. Mieczkowski,Lisle E. Mose,Joel S. Parker,Charles M. Perou,Jan F. Prins,Jeffrey Roach,Yan Shi,Janae V. Simons,Darshan Singh,Matthew G. Soloway,Donghui Tan,Umadevi Veluvolu,Vonn Walter,Scot Waring,Matthew D. Wilkerson,Junyuan Wu,Ni Zhao,Andrew D. Cherniack,Peter S. Hammerman,Aaron D. Tward,Chandra Sekhar Pedamallu,Gordon Saksena,Joonil Jung,Akinyemi I. Ojesina,Scott L. Carter,Travis I. Zack,Steven E. Schumacher,Rameen Beroukhim,Samuel S. Freeman,Matthew Meyerson,Juok Cho,Michael S. Noble,Daniel DiCara,Hailei Zhang,David I. Heiman,Nils Gehlenborg,Doug Voet,Pei Lin,Scott Frazer,Petar Stojanov,Yingchun Liu,Lihua Zou,Jaegil Kim,Donna M. Muzny,Harshavardhan Doddapaneni,Christie Kovar,Jeffrey S. Reid,Donna Morton,Yi Han,Walker Hale,Hsu Chao,Kyle Chang,Jennifer Drummond,Richard A. Gibbs,Nipun Kakkar,David A. Wheeler,Liu Xi,Giovanni Ciriello,Marc Ladanyi,William Lee,Ricardo Ramirez,Chris Sander,Ronglai Shen,Rileen Sinha,Nils Weinhold,Barry S. Taylor,B. Arman Aksoy,Gideon Dresdner,Jianjiong Gao,Benjamin Gross,Anders Jacobsen,Boris Reva,Nikolaus Schultz,S. Onur Sumer,Yichao Sun,Timothy A. Chan,Luc G. T. Morris,Joshua M. Stuart,Stephen C. Benz,Sam Ng,Christopher C. Benz,Christina Yau,Stephen B. Baylin,Leslie Cope,Ludmila Danilova,James G. Herman,Moiz S. Bootwalla,Dennis T. Maglinte,Peter W. Laird,Timothy J. Triche,Daniel J. Weisenberger,David Van Den Berg,Nishant Agrawal,Justin A. Bishop,Paul C. Boutros,Jeff Bruce,Lauren Averett Byers,Joseph A. Califano,Thomas E. Carey,Zhong Chen,Hui Cheng,Simion I. Chiosea,Ezra E.W. Cohen,Brenda Diergaarde,Ann Marie Egloff,Adel K. El-Naggar,Robert L. Ferris,Mitchell J. Frederick,Jennifer R. Grandis,Yan Guo,Robert I. Haddad,Thomas M. Harris,Angela B.Y. Hui,J. Jack Lee,Scott M. Lippman,Fei-Fei Liu,Jonathan B. McHugh,Jeffrey N. Myers,Patrick Kwok Shing Ng,Bayardo Perez-Ordonez,Curtis R. Pickering,Michael B. Prystowsky,Marjorie Romkes,Anthony Saleh,Maureen A. Sartor,Raja R. Seethala,Tanguy Y. Seiwert,Han Si,Carter Van Waes,Daryl Waggott,Maciej Wiznerowicz,Wendell G. Yarbrough,Jiexin Zhang,Zhixiang Zuo,Ken Burnett,Daniel Crain,Johanna Gardner,Kevin Lau,David Mallery,Scott Morris,Joseph Paulauskis,Robert Penny,Candace Shelton,Troy Shelton,Mark E. Sherman,Peggy Yena,Aaron D. Black,Jay Bowen,Jessica Frick,Julie M. Gastier-Foster,Hollie A. Harper,Kristen M. Leraas,Tara M. Lichtenberg,Nilsa C. Ramirez,Lisa Wise,Erik Zmuda,Julien Baboud,Mark A. Jensen,Ari B. Kahn,Todd Pihl,David Pot,Deepak Srinivasan,Jessica Walton,Yunhu Wan,Robert A. Burton,Tanja Davidsen,John A. Demchok,Greg Eley,Martin L. Ferguson,Kenna R. Mills Shaw,Bradley A. Ozenberger,Margi Sheth,Heidi J. Sofia,Roy Tarnuzzer,Zhining Wang,Liming Yang,Jean C. Zenklusen,Charles Saller,Katherine Tarvin,Chu Chen,Roni J. Bollag,Paul M. Weinberger,Wojciech Golusiński,Paweł Golusiński,Matthew Ibbs,Konstanty Korski,Andrzej Mackiewicz,Wiktoria Maria Suchorska,Bartosz Szybiak,Erin Curley,Christina Beard,Colleen Mitchell,George E. Sandusky,Julie Ahn,Zubair Khan,Jonathan C. Irish,John Waldron,William N. William,Sophie C. Egea,Carmen Gomez-Fernandez,Lynn M. Herbert,Carol R. Bradford,Douglas B. Chepeha,Andrea Haddad,Tamara R. Jones,Christine M. Komarck,Mayya Malakh,Jeffrey S. Moyer,Ariane Nguyen,Lisa A. Peterson,Mark E. Prince,Laura S. Rozek,Evan G. Taylor,Heather M. Walline,Gregory T. Wolf,Lori Boice,Bhishamjit S. Chera,William K. Funkhouser,Margaret L. Gulley,Trevor Hackman,Michele C. Hayward,Mei Huang,W. Kimryn Rathmell,Ashley H. Salazar,William W. Shockley,Carol G. Shores,Leigh B. Thorne,Mark C. Weissler,Sylvia Wrenn,Adam M. Zanation,Brandee T. Brown,Michelle Q. Pham +309 more
TL;DR: It is shown that human-papillomavirus-associated tumours are dominated by helical domain mutations of the oncogene PIK3CA, novel alterations involving loss of TRAF3, and amplification of the cell cycle gene E2F1.
Journal ArticleDOI
Everolimus in Postmenopausal Hormone-Receptor–Positive Advanced Breast Cancer
José Baselga,Mario Campone,Martine Piccart,Howard A. Burris,Hope S. Rugo,Tarek Sahmoud,Shinzaburo Noguchi,Michael Gnant,Kathleen I. Pritchard,Fabienne Lebrun,J. Thaddeus Beck,Yoshinori Ito,Denise A. Yardley,Ines Deleu,Alejandra T. Perez,Thomas Bachelot,L. Vittori,Zhiying Xu,Pabak Mukhopadhyay,David Lebwohl,Gabriel N. Hortobagyi +20 more
TL;DR: Everolimus combined with an aromatase inhibitor improved progression-free survival in patients with hormone-receptor-positive advanced breast cancer previously treated with nonsteroidal aromat enzyme inhibitors.
Journal ArticleDOI
Exploiting the PI3K/AKT Pathway for Cancer Drug Discovery
TL;DR: Recent studies indicate that numerous components of the phosphatidylinositol-3-kinase (PI3K)/AKT pathway are targeted by amplification, mutation and translocation more frequently than any other pathway in cancer patients, with resultant activation of the pathway.