Isoform-specific phosphoinositide 3-kinase inhibitors exert distinct effects in solid tumors

Cancer Research
Kyle A EdgarMarcia Belvin

Abstract

Therapeutic inhibitors are being developed against the phosphoinositide 3-kinase (PI3K) pathway, the deregulation of which drives tumor growth and survival in many cancers. There are eight PI3Ks in mammals divided into three classes. Class IA PI3Ks (p110alpha, p110beta, and p110delta) are critical for cell growth and survival, with the p110alpha isoform implicated as the most important in carcinomas. In this study, we examined the effects of small-molecule inhibitors of class IA PI3Ks to explore the contributions of different isoforms in cancer cells. Similar responses were seen in cancer cells with wild-type or activated mutant PI3K genes treated with p110alpha/delta or p110alpha/beta/delta inhibitors in cell viability assays. In contrast, PTEN-negative cell lines tended to be less responsive (4-fold overall) to an inhibitor of p110alpha/delta versus p110alpha/beta/delta. Combining a p110alpha/delta inhibitor with a p110beta inhibitor resulted in comparable potency to the p110alpha/beta/delta inhibitor. The disparity in efficacy was confirmed in vivo. Pharmacodynamic biomarker analysis revealed that an inhibitor with insufficient potency against the p110beta isoform was less effective at inhibiting the PI3K pathway in PTEN-neg...Continue Reading

References

Sep 22, 2000·The Biochemical Journal·S P DaviesP Cohen
Jun 1, 2002·Science·Lewis C Cantley
Jul 12, 2002·Genes, Chromosomes & Cancer·Bertrand ActorRuthild G Weber
Feb 6, 2003·International Journal of Cancer. Journal International Du Cancer·Do-Sun ByunSung-Gil Chi
Aug 21, 2003·Biochemical and Biophysical Research Communications·Chanchal SadhuDonald E Staunton
Mar 16, 2004·Science·Yardena SamuelsVictor E Velculescu
Nov 3, 2004·Cancer Research·Ian G CampbellWayne A Phillips
Apr 19, 2005·Nature Medicine·Shaun P JacksonHatem H Salem
Sep 15, 2005·Gynecologic Oncology·Chad A LivasyRuth A Lininger
Nov 16, 2005·International Journal of Cancer. Journal International Du Cancer·Bjørn I BertelsenOle Didrik Laerum
Dec 13, 2005·Nature Reviews. Cancer·Andreas G BaderPeter K Vogt
Oct 21, 2006·Biochemical Society Transactions·P T HawkinsL R Stephens
Nov 23, 2006·Science's STKE : Signal Transduction Knowledge Environment·Domingo F BarberAna C Carrera
Jun 12, 2008·Proceedings of the National Academy of Sciences of the United States of America·Julie Guillermet-GuibertBart Vanhaesebroeck
Aug 30, 2008·Current Opinion in Pharmacology·Timothy A YapPaul Workman
Aug 30, 2008·Proceedings of the National Academy of Sciences of the United States of America·Susan WeeChristoph Lengauer
Dec 17, 2008·Recent Patents on Inflammation & Allergy Drug Discovery·Alessandra Ghigo, Emilio Hirsch
Jul 29, 2009·Molecular and Cellular Biology·Rosalia RabinovskyWilliam R Sellers

❮ Previous
Next ❯

Citations

Jul 31, 2013·Acta Pharmacologica Sinica·Xiang WangLing-hua Meng
Feb 13, 2013·Nature Reviews. Clinical Oncology·Jordi RodonJosep Tabernero
Mar 6, 2013·Nature Reviews. Clinical Oncology·Dimitrios ZardavasMartine Piccart
Jan 1, 2013·The Journal of Biological Chemistry·Lomon SoDavid A Fruman
Sep 18, 2013·The Journal of Experimental Medicine·Adriana SolerBart Vanhaesebroeck
Mar 29, 2012·The Cancer Journal·Michael A Davies
May 16, 2013·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Britta WeigeltJulian Downward
Mar 5, 2013·Endocrine-related Cancer·Rhonda L Bitting, Andrew J Armstrong
Dec 3, 2014·Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences·Yuzhong DengBrian Dean
Jan 26, 2016·Pharmacogenomics·Lydia Wt Cheung, Gordon B Mills
Jun 29, 2015·Current Opinion in Pharmacology·Timothy A YapPaul Workman
Sep 17, 2011·Drug Resistance Updates : Reviews and Commentaries in Antimicrobial and Anticancer Chemotherapy·Ranee MehraErica A Golemis
Nov 3, 2010·Advances in Enzyme Regulation·Marie-Pierre GratacapBernard Payrastre
Jan 19, 2012·British Journal of Pharmacology·Joost C M UitdehaagGuido J R Zaman
Aug 16, 2014·International Journal of Cancer. Journal International Du Cancer·Lisa NonnenmacherKlaus-Michael Debatin
Aug 1, 2015·Nature Communications·Helena SerraMariona Graupera
May 18, 2013·Cancer Cell·Bijay S JaiswalSomasekar Seshagiri
Nov 20, 2014·Nature·Dejan JuricMaurizio Scaltriti
Jul 31, 2010·Molecular Cancer·Alberto Ocaña, Atanasio Pandiella
May 14, 2016·Journal of Experimental & Clinical Cancer Research : CR·Hua-Fu ZhaoShing-Shun Tony To
May 6, 2016·Journal of Cellular Biochemistry·Mary D ChamberlinTodd W Miller
Nov 12, 2016·Cancer Chemotherapy and Pharmacology·Emma J HaagensenDavid R Newell
Jan 3, 2019·Endocrinology·Anne R Bresnick, Jonathan M Backer
Mar 15, 2012·British Journal of Cancer·E J HaagensenD R Newell
Jun 12, 2010·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Laurent SalphatiJeffrey J Wallin
Dec 19, 2017·Expert Opinion on Investigational Drugs·Niamh M KeeganPatrick G Morris

❮ Previous
Next ❯

Related Concepts

Related Feeds

AKT Pathway

This feed focuses on the AKT serine/threonine kinase, which is an important signaling pathway involved in processes such as glucose metabolism and cell survival.