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Mutations and deregulation of Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR cascades which alter therapy response

James A McCubrey1, Linda S Steelman, William H Chappell

  • 1Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC, USA. mccubreyj@ecu.edu

Oncotarget
|September 26, 2012
PubMed

Insights

Genetic alterations in the Ras/Raf/MEK/ERK and PI3K/Akt/mTOR pathways can lead to drug resistance. Understanding these signaling cascades is crucial for developing effective cancer therapies.

Area of Science:

  • Molecular Biology
  • Cell Signaling
  • Oncology

Background:

  • The Ras/Raf/MEK/ERK and PI3K/Akt/mTOR pathways are critical regulators of cell proliferation, survival, and differentiation.
  • These pathways are frequently dysregulated in various cancers due to genetic alterations in upstream signaling molecules like receptor tyrosine kinases (RTKs).
  • Components within these cascades, including RAS, BRAF, PIK3CA, AKT, and mTOR, can be activated or inactivated by mutations or epigenetic modifications.

Purpose of the Study:

  • To review the Ras/Raf/MEK/ERK and PI3K/Akt/mTOR signaling pathways.
  • To discuss how genetic mutations and epigenetic alterations in these pathways contribute to drug resistance.
  • To explore the implications of pathway dysregulation in diseases beyond cancer, such as premature aging.

Main Methods:

  • Literature review of scientific articles on cell signaling pathways.
  • Analysis of genetic and epigenetic alterations affecting key pathway components.
  • Discussion of the impact of these alterations on cellular processes and drug sensitivity.

Main Results:

  • Genetic alterations in RTKs and pathway components (e.g., RAS, BRAF, PIK3CA, AKT, mTOR) are common drivers of cancer.
  • Mutations and epigenetic silencing within these pathways can confer resistance to targeted therapies and chemotherapeutics.
  • Dysregulation of these cascades is linked to various diseases, including premature aging syndromes.

Conclusions:

  • Understanding the intricate mechanisms of Ras/Raf/MEK/ERK and PI3K/Akt/mTOR pathway activation and dysregulation is essential for overcoming therapeutic resistance.
  • Targeting specific components or combinations of components within these pathways holds promise for novel cancer treatment strategies.
  • Further research into the broader implications of these signaling pathways may reveal new therapeutic targets for a range of diseases.

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