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Signal Transduction Pathways as Therapeutic Targets in Cancer Therapy

  • Michele Milella
  • Ludovica Ciuffreda
  • Emilio Bria
Chapter
Part of the Macromolecular Anticancer Therapeutics book series (CDD&D)

Abstract

Cancer is increasingly recognized as “miscommunication” disease, in which inter- and intracellular signals are aberrantly sent and/or received, resulting in the uncontrolled proliferation, survival, and invasiveness of the cancer cell. Indeed, many of the genetic and epigenetic aberrations, which underlie the process of neoplastic transformation and progression, ultimately impinge on the inappropriate activation/inactivation of intracellular signaling pathways. Such signaling cascades usually proceed from the cell surface, where growth factors interact with their specific receptors, to cytoplasmic signaling intermediates, where different signals are integrated and both positive and negative feedback circuitry are in place to ensure signal fidelity and transduction accuracy, to nuclear transcription factors/complexes, which ultimately lead to the transcription/translation of effector genes and proteins involved in specific cellular functions. While the signal may be inappropriately transduced at several, and usually multiple, levels, one interesting feature of aberrant cancer signaling is that cancer cells may become “addicted” to specific signals and hence exquisitely sensitive to their modulation. In this chapter we will describe the signaling process, highlighting the steps at which aberrant signal transduction may turn a normal cell into a cancer cell and the crucial points where aberrant signals can be modulated for therapeutic purposes. Finally, we will briefly touch upon relevant issues surrounding the clinical development of signal transduction inhibitors as anticancer agents.

Keywords

Epidermal Growth Factor Receptor Chronic Myelogenous Leukemia Epidermal Growth Factor Receptor Mutation Tuberous Sclerosis Complex PIK3CA Mutation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Abbreviations

ALL

acute lymphocytic leukemia

AML

acute myeloid leukemia

AMPK

AMP-activated protein kinase

ASK1

apoptosis signal kinase 1

ATP

adenosine triphosphate

BSC

best supportive care

Cdk

cyclin-dependent kinase(s)

CFC

cardio-facio-cutaneous syndrome

CML

chronic myelogenous leukemia

4EBP1

eukaryotic translation initiation factor 4E binding protein 1

EGFR

epidermal growth factor receptor

ERK

extracellular-signal-regulated kinase

FISH

fluorescence in situ hybridization

FLT3

Fms-like tyrosine kinase 3

GIST

gastrointestinal stromal tumor(s)

GSK3

glycogen synthase kinase 3

Hsp

heat-shock protein

IRS

Insulin receptor substrate

JNK

Jun N-terminal kinase

LAM

Lymphangioleiomyomatosis

MAPK

mitogen-activated protein kinase

MEK

MAPK and ERK kinase

MITF

microphthalmia transcription factor

MST-2

mammalian sterile 20-like kinase

mTOR(C)

mammalian target of rapamycin (complex)

NF1

neurofibromatosis 1

NSCLC

non-small cell lung cancer

PDGF

platelet-derived growth factor

PDK1

3-phosphoinositide-dependent protein kinase 1

PH

pleckstrin homology domain

PI3K

phosphoinositide 3-kinase

PI3K

AKT (phosphatidylinositol-3 kinase–AKT)

PTEN

phosphatase and tensin homolog deleted on chromosome 10

Raptor

regulatory-associated protein of mTOR

Ras–Raf–MEK

(mitogen-activated and extracellular-signal-regulated kinase kinase)

Rheb

Ras homolog enriched in brain

Rictor

rapamycin-insensitive companion of mTOR

RNAi

RNA interference

ROS

reactive oxygen species

RTK

receptor tyrosine kinase(s)

S6K1

ribosomal S6 kinase 1

SCLC

small cell lung cancer

STAT

signal transducer and activator of transcription

t-AML

therapy-induced AML

TGFa

transforming growth factor a

TK

protein tyrosine kinase(s)

TKI

tyrosine kinase inhibitor(s)

TNF

tumor necrosis factor

TSC

tuberous sclerosis complex

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Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Michele Milella
    • 1
  • Ludovica Ciuffreda
    • 1
  • Emilio Bria
    • 1
  1. 1.Division of Medical Oncology A (MM and LC) and C (EB)Regina Elena National Cancer InstituteRomeItaly

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