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Vertical targeting of the phosphatidylinositol-3 kinase pathway as a strategy for treating melanoma

Saadia A Aziz1, Lucia B Jilaveanu, Christopher Zito

  • 1Department of Pathology, Yale University School of Medicine, Yale Cancer Center, New Haven, Connecticut 06510, USA.

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
|December 21, 2010
PubMed
Abstract

Insights

Targeting mTOR alongside PI3K shows promise for melanoma treatment. A dual PI3K/mTOR inhibitor demonstrated significant in vitro activity, suggesting combined targeting warrants further investigation for improved melanoma therapies.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Melanoma exhibits resistance to conventional chemotherapy, necessitating novel therapeutic targets.
  • Phosphatidylinositol-3 kinase (PI3K) is a key target in melanoma, but PI3K inhibitors (PI3KI) have shown limited efficacy.
  • The mammalian target of rapamycin (mTOR) is being investigated as a potential cotarget to enhance PI3K inhibition.

Purpose of the Study:

  • To evaluate the role of mTOR as a cotarget in combination with PI3K inhibition for melanoma treatment.
  • To assess the coexpression of mTOR and PI3K subunits (p85 and p110α) in melanoma.
  • To investigate the in vitro efficacy of a novel dual PI3K/mTOR inhibitor and its combination with a MEK inhibitor.

Main Methods:

  • Quantitative immunofluorescence was used to measure mTOR expression and its association with PI3K subunits in a melanoma cohort.
  • The effects of adding the mTOR inhibitor rapamycin to two PI3KIs (NVP-BKM120 and LY294002) were assessed.
  • In vitro activity of a dual PI3K/mTOR inhibitor (NVP-BEZ235) and its combination with a MEK inhibitor (AZD6244) were evaluated.

Main Results:

  • Strong coexpression was observed between mTOR and the PI3K p110α subunit (ρ = 0.658, P < 0.0001).
  • Rapamycin demonstrated significant synergism with both PI3KIs, enhancing their activity.
  • The dual PI3K/mTOR inhibitor NVP-BEZ235 effectively reduced melanoma cell viability and clonogenicity, downregulating pAkt and pP70S6K.
  • Combining NVP-BEZ235 with AZD6244 showed synergistic effects, indicated by increased poly(ADP-ribose) polymerase and caspase-2 cleavage.

Conclusions:

  • mTOR and PI3K p110α are coexpressed in melanoma, supporting their cotargeting.
  • Low concentrations of rapamycin can enhance PI3KI activity.
  • The dual PI3K/mTOR inhibitor NVP-BEZ235 exhibits potent in vitro activity against melanoma cells.
  • Concurrent targeting of PI3K and mTOR, alone or with MEK inhibitors, warrants further clinical investigation for melanoma treatment.

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