Akt inhibitors MK-2206 and nelfinavir overcome mTOR inhibitor resistance in diffuse large B-cell lymphoma.

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
Adam M PetrichSamir Parekh

Abstract

The mTOR pathway is constitutively activated in diffuse large B-cell lymphoma (DLBCL). mTOR inhibitors have activity in DLBCL, although response rates remain low. We evaluated DLBCL cell lines with differential resistance to the mTOR inhibitor rapamycin: (i) to identify gene expression profile(s) (GEP) associated with resistance to rapamycin, (ii) to understand mechanisms of rapamycin resistance, and (iii) to identify compounds likely to synergize with mTOR inhibitor. We sought to identify a GEP of mTOR inhibitor resistance by stratification of eight DLBCL cell lines with respect to response to rapamycin. Then, using pathway analysis and connectivity mapping, we sought targets likely accounting for this resistance and compounds likely to overcome it. We then evaluated two compounds thus identified for their potential to synergize with rapamycin in DLBCL and confirmed mechanisms of activity with standard immunoassays. We identified a GEP capable of reliably distinguishing rapamycin-resistant from rapamycin-sensitive DLBCL cell lines. Pathway analysis identified Akt as central to the differentially expressed gene network. Connectivity mapping identified compounds targeting Akt as having a high likelihood of reversing the GEP asso...Continue Reading

References

Dec 1, 1995·Therapeutic Drug Monitoring·S N Sehgal
May 1, 1997·Journal of Clinical Pharmacology·J J Zimmerman, B D Kahan
Mar 19, 2004·Nature·Hans-Guido WendelScott W Lowe
Oct 27, 2004·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Xiaoyan ZhouDihua Yu
Oct 27, 2004·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Odile DavidArnold R Brody
Aug 16, 2005·Blood·Willis H Navarro, Lawrence D Kaplan
May 2, 2006·Statistical Applications in Genetics and Molecular Biology·Gordon K Smyth
Jun 1, 2007·The New England Journal of Medicine·Gary HudesUNKNOWN Global ARCC Trial
Aug 19, 2007·Annals of Oncology : Official Journal of the European Society for Medical Oncology·M BeeramL A DeGraffenried
Sep 6, 2007·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Joell J GillsPhillip A Dennis
Feb 21, 2008·Cancer Biology & Therapy·John P PlastarasAnjali K Gupta
Mar 26, 2008·BioTechniques·Mark AbramovitzBrian Leyland-Jones
May 16, 2008·Bioorganic & Medicinal Chemistry Letters·Mark T BilodeauGeorge D Hartman
Sep 2, 2008·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Antonio JimenoManuel Hidalgo
Oct 15, 2008·Molecular Cancer Therapeutics·Richard F RiedelPhillip G Febbo
Nov 29, 2008·The New England Journal of Medicine·G LenzUNKNOWN Lymphoma/Leukemia Molecular Profiling Project
May 13, 2009·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Carolyn D SeibBrent T Shoji
Jul 8, 2009·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Georg HessBertrand Coiffier
Aug 25, 2009·Best Practice & Research. Clinical Haematology·Javeed IqbalWing C Chan
Oct 7, 2009·Proceedings of the National Academy of Sciences of the United States of America·Martin L SosRoman K Thomas
Jan 9, 2010·Seminars in Oncology·Georg HessBertrand Coiffier
Sep 15, 2010·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Sonali M SmithBarbara Pro

❮ Previous
Next ❯

Citations

Feb 3, 2012·Current Treatment Options in Oncology·Murali JanakiramAdam M Petrich
Nov 13, 2013·Nature Reviews. Clinical Oncology·Mark RoschewskiWyndham H Wilson
Sep 13, 2014·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Agata MajchrzakPiotr Smolewski
Jul 28, 2015·British Journal of Haematology·Yasuhiro OkiAnas Younes
May 21, 2014·British Journal of Haematology·Toby A EyreKate Cwynarski
Dec 7, 2013·Journal of Hepatology·Matthias S MatterSnorri S Thorgeirsson
Jun 20, 2015·Medical Oncology·Jeng-Wei LuLiang-In Lin
Aug 1, 2015·Blood Cells, Molecules & Diseases·Kamil BojarczukMagdalena Winiarska
Dec 20, 2014·Future Oncology·Lohith S Bachegowda, Stefan K Barta
Feb 9, 2016·AIDS·David C BoettigerUNKNOWN Data collection on Adverse events of Anti-HIV Drugs (D:A:D) study group
Jan 26, 2016·British Journal of Clinical Pharmacology·Jong-Hoon Scott LeeDavid A Fruman
Jun 20, 2017·The American Journal of Pathology·Jinfen WangKen H Young
Jun 1, 2017·Journal of Drug Targeting·Siying ChenYalin Dong
Sep 25, 2017·Arthritis & Rheumatology·Cecilia G SanchezJoseph A Lasky
May 2, 2020·Cells·Burkitkan AkbaySvetlana Dokudovskaya
Mar 4, 2014·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Marina Y KonoplevaHagop M Kantarjian
Nov 2, 2013·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Violetta V LeshchenkoSamir Parekh
Nov 25, 2020·Cancers·Mahbuba R Subeha, Carlos M Telleria
May 22, 2021·Cell Communication and Signaling : CCS·Mehrshad Sadria, Anita T Layton

❮ Previous
Next ❯

Related Concepts

Related Feeds

Cancer Genomics (Keystone)

Cancer genomics approaches employ high-throughput technologies to identify the complete catalog of somatic alterations that characterize the genome, transcriptome and epigenome of cohorts of tumor samples. Discover the latest research using such technologies in this feed.

B-Cell Lymphoma

B-cell lymphomas include lymphomas that affect B cells. This subtype of cancer accounts for over 80% of non-Hodgkin lymphomas in the US. Here is the latest research.

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.

Related Papers

The Journal of Biological Chemistry
Hana Totary-JainAndrew R Marks
Hepatology : Official Journal of the American Association for the Study of Liver Diseases
Hongping XiaKam M Hui
European Journal of Cancer : Official Journal for European Organization for Research and Treatment of Cancer (EORTC) [and] European Association for Cancer Research (EACR)
Clemens UngerKlaus Mross
© 2022 Meta ULC. All rights reserved