A-674563, a putative AKT1 inhibitor that also suppresses CDK2 activity, inhibits human NSCLC cell growth more effectively than the pan-AKT inhibitor, MK-2206

PloS One
Paige M Chorner, Roger A Moorehead

Abstract

AKT is a serine-threonine kinase implicated in tumorigenesis as a central regulator of cellular growth, proliferation, survival, and metabolism. Activated AKT is commonly overexpressed in non-small cell lung cancer (NSCLC) and accordingly AKT inhibitors are under clinical investigation for NSCLC treatment. Thus far, the AKT inhibitors being evaluated broadly target all three (1-3) AKT isoforms but recent evidence suggests opposing roles in lung tumorigenesis where loss of Akt1 inhibits while the loss of Akt2 enhances lung tumor development. Based on these findings, we hypothesized that selective inhibition of AKT-1 would be a more effective therapeutic strategy than pan-AKT inhibition for NSCLC treatment. Using six NSCLC cell lines, we found that the AKT-1 inhibitor, A-674563, was significantly more effective at reducing NSCLC cell survival relative to the pan-AKT inhibitor MK-2206. Comparison of the downstream effects of the inhibitors suggests that altered cell cycle progression and off-target CDK2 inhibition are likely vital to the improved efficacy of A-674563 over MK-2206.

References

May 1, 1987·British Journal of Cancer·D VealeA L Harris
Jun 5, 2003·The Journal of Biological Chemistry·Zhong-Zhou YangBrian A Hemmings
Jul 1, 2004·Molecular and Cellular Biology·Yonghong ZhuEmma Lees
Dec 7, 2005·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Junji TsurutaniPhillip A Dennis
Mar 28, 2007·Molecular Cell·Yasemin SancakDavid M Sabatini
May 19, 2007·The Journal of Biological Chemistry·Lifu WangJohn C Lawrence
Jun 1, 2007·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Federico CappuzzoMarileila Varella-Garcia
Jul 3, 2007·The Journal of Biological Chemistry·Bruno D FonsecaChristopher G Proud
Jul 3, 2008·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Jussi P KoivunenPasi A Jänne
Oct 25, 2008·Nature·Li DingRichard K Wilson
Apr 18, 2009·Proceedings of the National Academy of Sciences of the United States of America·Eva Gonzalez, Timothy E McGraw
Jul 15, 2009·Cell Cycle·Eva Gonzalez, Timothy E McGraw
Apr 7, 2010·Cancer Biology & Therapy·Xiaoyan LiangXiaohong Tao
Jan 24, 2012·Developmental Cell·Cristina Pallares-CartesAurelio A Teleman
Feb 23, 2012·American Journal of Physiology. Endocrinology and Metabolism·Claudia WizaD Margriet Ouwens
Apr 12, 2014·PloS One·Nicolle M Linnerth-PetrikSarah K Wootton
Sep 19, 2014·Biochemical Society Transactions·Abbe R Clark, Alex Toker
Oct 18, 2014·Journal of Cancer Research and Clinical Oncology·William S HollandPhilip C Mack
Jan 7, 2015·CA: a Cancer Journal for Clinicians·Rebecca L SiegelAhmedin Jemal
Jun 25, 2015·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Primo N LaraDavid R Gandara
Aug 22, 2015·Journal of Chemotherapy·Maryam OladghaffariAli Shabestani Monfared
Dec 15, 2015·Oncotarget·S Elizabeth FranksRoger A Moorehead

❮ Previous
Next ❯

Citations

Jul 24, 2018·Oncotarget·Atrayee BhattacharyaArchana Dhasarathy
Feb 19, 2020·Biotechnology and Applied Biochemistry·Meenakshisundaram BalasubramaniamPrasanna Rajagopalan
Apr 12, 2021·Neoplasia : an International Journal for Oncology Research·Jeremy JohnsonPiotr Rychahou
May 2, 2021·Molecular Cancer Research : MCR·Seamus E Degan, Irwin H Gelman

❮ Previous
Next ❯

Methods Mentioned

BETA
transgenic
PCR
Electrophoresis
flow cytometry

Software Mentioned

GraphPad
Manager
Graphpad Prism
CalcuSyn
Image Lab
CFX
Accuri C6

Related Concepts

Related Feeds

Apoptosis

Apoptosis is a specific process that leads to programmed cell death through the activation of an evolutionary conserved intracellular pathway leading to pathognomic cellular changes distinct from cellular necrosis

Apoptosis in Cancer

Apoptosis is an important mechanism in cancer. By evading apoptosis, tumors can continue to grow without regulation and metastasize systemically. Many therapies are evaluating the use of pro-apoptotic activation to eliminate cancer growth. Here is the latest research on apoptosis in cancer.

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.