Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR Inhibitors: Rationale and Importance to Inhibiting These Pathways in Human Health

There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

Abstract

The Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR cascades are often activated by genetic alterations in upstream signaling molecules such as receptor tyrosine kinases (RTK). Integral components of these pathways, Ras, B-Raf, PI3K, and PTEN are also activated/inactivated by mutations. These pathways have profound effects on proliferative, apoptotic and differentiation pathways. Dysregulation of these pathways can contribute to chemotherapeutic drug resistance, proliferation of cancer initiating cells (CICs) and premature aging. This review will evaluate more recently described potential uses of MEK, PI3K, Akt and mTOR inhibitors in the proliferation of malignant cells, suppression of CICs, cellular senescence and prevention of aging. Ras/Raf/MEK/ERK and Ras/PI3K/PTEN/Akt/mTOR pathways play key roles in the regulation of normal and malignant cell growth. Inhibitors targeting these pathways have many potential uses from suppression of cancer, proliferative diseases as well as aging.

Related collections

Most cited references 254

Record: found
Abstract: found
Article: not found

Specificity and mechanism of action of some commonly used protein kinase inhibitors.

S. P. Davies, H. Reddy, M Caivano … (2000)

The specificities of 28 commercially available compounds reported to be relatively selective inhibitors of particular serine/threonine-specific protein kinases have been examined against a large panel of protein kinases. The compounds KT 5720, Rottlerin and quercetin were found to inhibit many protein kinases, sometimes much more potently than their presumed targets, and conclusions drawn from their use in cell-based experiments are likely to be erroneous. Ro 318220 and related bisindoylmaleimides, as well as H89, HA1077 and Y 27632, were more selective inhibitors, but still inhibited two or more protein kinases with similar potency. LY 294002 was found to inhibit casein kinase-2 with similar potency to phosphoinositide (phosphatidylinositol) 3-kinase. The compounds with the most impressive selectivity profiles were KN62, PD 98059, U0126, PD 184352, rapamycin, wortmannin, SB 203580 and SB 202190. U0126 and PD 184352, like PD 98059, were found to block the mitogen-activated protein kinase (MAPK) cascade in cell-based assays by preventing the activation of MAPK kinase (MKK1), and not by inhibiting MKK1 activity directly. Apart from rapamycin and PD 184352, even the most selective inhibitors affected at least one additional protein kinase. Our results demonstrate that the specificities of protein kinase inhibitors cannot be assessed simply by studying their effect on kinases that are closely related in primary structure. We propose guidelines for the use of protein kinase inhibitors in cell-based assays.

0 comments Cited 581 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Intrinsic resistance of tumorigenic breast cancer cells to chemotherapy.

Xiaoxian Li, Michael Lewis, Jian Huang … (2008)

Tumorigenic breast cancer cells that express high levels of CD44 and low or undetectable levels of CD24 (CD44(>)/CD24(>/low)) may be resistant to chemotherapy and therefore responsible for cancer relapse. These tumorigenic cancer cells can be isolated from breast cancer biopsies and propagated as mammospheres in vitro. In this study, we aimed to test directly in human breast cancers the effect of conventional chemotherapy or lapatinib (an epidermal growth factor receptor [EGFR]/HER2 pathway inhibitor) on this tumorigenic CD44(>) and CD24(>/low) cell population. Paired breast cancer core biopsies were obtained from patients with primary breast cancer before and after 12 weeks of treatment with neoadjuvant chemotherapy (n = 31) or, for patients with HER2-positive tumors, before and after 6 weeks of treatment with the EGFR/HER2 inhibitor lapatinib (n = 21). Single-cell suspensions established from these biopsies were stained with antibodies against CD24, CD44, and lineage markers and analyzed by flow cytometry. The potential of cells from biopsy samples taken before and after treatment to form mammospheres in culture was compared. All statistical tests were two-sided. Chemotherapy treatment increased the percentage of CD44(>)/CD24(>/low) cells (mean at baseline vs 12 weeks, 4.7%, 95% confidence interval [CI] = 3.5% to 5.9%, vs 13.6%, 95% CI = 10.9% to 16.3%; P )/CD24(>/low) cells (mean at baseline vs 6 weeks, 10.0%, 95% CI = 7.2% to 12.8%, vs 7.5%, 95% CI = 4.1% to 10.9%) and a statistically non-significant decrease in MSFE (mean at baseline vs 6 weeks, 16.1%, 95% CI = 8.7% to 23.5%, vs 10.8%, 95% CI = 4.0% to 17.6%). These studies provide clinical evidence for a subpopulation of chemotherapy-resistant breast cancer-initiating cells. Lapatinib did not lead to an increase in these tumorigenic cells, and, in combination with conventional therapy, specific pathway inhibitors may provide a therapeutic strategy for eliminating these cells to decrease recurrence and improve long-term survival.

0 comments Cited 567 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Identification of a novel inhibitor of mitogen-activated protein kinase kinase.

M Favata, K Y Horiuchi, E. J. Manos … (1998)

The compound U0126 (1,4-diamino-2,3-dicyano-1, 4-bis[2-aminophenylthio]butadiene) was identified as an inhibitor of AP-1 transactivation in a cell-based reporter assay. U0126 was also shown to inhibit endogenous promoters containing AP-1 response elements but did not affect genes lacking an AP-1 response element in their promoters. These effects of U0126 result from direct inhibition of the mitogen-activated protein kinase kinase family members, MEK-1 and MEK-2. Inhibition is selective for MEK-1 and -2, as U0126 shows little, if any, effect on the kinase activities of protein kinase C, Abl, Raf, MEKK, ERK, JNK, MKK-3, MKK-4/SEK, MKK-6, Cdk2, or Cdk4. Comparative kinetic analysis of U0126 and the MEK inhibitor PD098059 (Dudley, D. T., Pang, L., Decker, S. J., Bridges, A. J., and Saltiel, A. R. (1995) Proc. Natl. Acad. Sci U. S. A. 92, 7686-7689) demonstrates that U0126 and PD098059 are noncompetitive inhibitors with respect to both MEK substrates, ATP and ERK. We further demonstrate that the two compounds bind to deltaN3-S218E/S222D MEK in a mutually exclusive fashion, suggesting that they may share a common or overlapping binding site(s). Quantitative evaluation of the steady state kinetics of MEK inhibition by these compounds reveals that U0126 has approximately 100-fold higher affinity for deltaN3-S218E/S222D MEK than does PD098059. We further tested the effects of these compounds on the activity of wild type MEK isolated after activation from stimulated cells. Surprisingly, we observe a significant diminution in affinity of both compounds for wild type MEK as compared with the deltaN3-S218E/S222D mutant enzyme. These results suggest that the affinity of both compounds is mediated by subtle conformational differences between the two activated MEK forms. The MEK affinity of U0126, its selectivity for MEK over other kinases, and its cellular efficacy suggest that this compound will serve as a powerful tool for in vitro and cellular investigations of mitogen-activated protein kinase-mediated signal transduction.

0 comments Cited 433 times – based on 0 reviews      Review now

Bookmark

All references

Author and article information

Journal

Journal ID (nlm-ta): Oncotarget

Journal ID (publisher-id): ImpactJ

Title: Oncotarget

Publisher: Impact Journals LLC

ISSN (Electronic): 1949-2553

Publication date Collection: March 2011

Publication date (Electronic): 11 March 2011

Volume: 2

Issue: 3

Pages: 135-164

Affiliations

¹ Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University

² Department of Physics, Greenville, NC 27858 USA

³ Department of Medicine University of Göttingen, Göttingen, Germany

⁴ Department of Biomedical Sciences, University of Catania, Catania, Italy

⁵ Department of Immunology, Institute for Biological Research “Sinisa Stankovic”, University of Belgrade, Belgrade, Serbia

⁶ Department of Internal Medicine and Specialties, University of Palermo, Palermo, Italy

⁷ Consiglio Nazionale delle Ricerche, Istituto di Biomedicina e Immunologia Molecolare “Alberto Monroy”, Palermo, Italy

⁸ Department of Medical Biochemistry Jagiellonian University Medical College, Krakow, Poland

⁹ Regina Elena Cancer Center, Via Elio Chianesi n.53, Rome 00144, Italy

¹⁰ University of Rome, La Sapienza, Department of Hematology-Oncology, Via Benevento 6, Rome 99161, Italy

¹¹ University Hospital of Parma, Unit of Hematology and Bone-Marrow Transplantation, Via Gramsi n.14, Parma 43100, Italy

¹² Dipartimento di Scienze Anatomiche Umane e Fisiopatologia dell'Apparato Locomotore, Università di Bologna, Bologna, Italy

¹³ IGM-CNR, Sezione di Bologna, C/o IOR, Bologna, Italy

Author notes

Correspondence to: James A. McCubrey, mccubreyj@ 123456ecu.edu

Article

DOI: 10.18632/oncotarget.240

PMC ID: 3260807

PubMed ID: 21411864

SO-VID: 4331b3ce-361d-4aa9-a8d9-a874d366be08

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

History

Date received : 25 February 2011

Date accepted : 10 March 2011

Comments

Comment on this article

scite_

Cited by 231

See all cited by

Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR Inhibitors: Rationale and Importance to Inhibiting These Pathways in Human Health

Read this article at

Abstract

Related collections

Karger: Oncology

Most cited references 254

Specificity and mechanism of action of some commonly used protein kinase inhibitors.

Intrinsic resistance of tumorigenic breast cancer cells to chemotherapy.

Identification of a novel inhibitor of mitogen-activated protein kinase kinase.

Author and article information

Journal

Affiliations

Author notes

Article

History

Categories

Comments

Comment on this article

Similar content 234

Cited by 231