Targeting the akt kinase to modulate survival, invasiveness and drug resistance of cancer cells

Giuliana Cassinelli, Valentina Zuco, Laura Gatti, Cinzia Lanzi, Nadia Zaffaroni, Diego Colombo, Paola Perego

Research output: Contribution to journalArticle

63 Citations (Scopus)

Abstract

The deregulation of oncogenic signaling pathways which provide survival advantages to tumor cells is mediated by multiple cellular networks. Among them, the PI3K-Akt-mTOR axis, in particular the serine/threonine kinase Akt, is recognized as a key player. The kinase is hyperactivated due to a variety of mechanisms including loss of PTEN, mutations in the PI3K catalytic subunit, receptor tyrosine kinase and Ras activation. Indeed, inappropriate activation of the Akt kinase is a common event in human tumors and Akt appears to be a critical player in cell survival that may also account for the therapeutic resistance and the invasive phenotype of tumors. Inhibition of Akt signalling results in apoptosis and growth inhibition of tumour cells with elevated Akt activity. A functional role in drug resistance is supported by evidence that tumor cells with acquired resistance to antitumor agents may display increased Akt activation and that treatment with molecularly targeted agents can activate feed-back loops involving Akt. This serine/threonine kinase may therefore represent an amenable target for modulation of sensitivity to compounds with different molecular features due to its pleiotropic role in cell survival. Different types of Akt inhibitors [i.e., ATP mimetics and pleckstrin-homology (PH) domain binders] have been generated and some of them have reached the clinical setting. The present review focuses on the i) mechanisms implicating Akt in increased survival and invasive potential of tumor cells of different tumor types and ii) on the development of Akt inhibitors as modulators of drug resistance.

Original languageEnglish
Pages (from-to)1923-1945
Number of pages23
JournalCurrent Medicinal Chemistry
Volume20
Issue number15
DOIs
Publication statusPublished - May 2013

Fingerprint

Drug Resistance
Tumors
Phosphotransferases
Cells
Survival
Pharmaceutical Preparations
Neoplasms
Protein-Serine-Threonine Kinases
Chemical activation
Phosphatidylinositol 3-Kinases
Cell Survival
Deregulation
Receptor Protein-Tyrosine Kinases
Antineoplastic Agents
Modulators
Binders
Catalytic Domain
Adenosine Triphosphate
Modulation
Apoptosis

Keywords

  • Akt
  • Akt inhibitors
  • Angiogenesis
  • Drug resistance
  • Invasion

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

Cite this

Targeting the akt kinase to modulate survival, invasiveness and drug resistance of cancer cells. / Cassinelli, Giuliana; Zuco, Valentina; Gatti, Laura; Lanzi, Cinzia; Zaffaroni, Nadia; Colombo, Diego; Perego, Paola.

In: Current Medicinal Chemistry, Vol. 20, No. 15, 05.2013, p. 1923-1945.

Research output: Contribution to journalArticle

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