Role and therapeutic potential of PI3K-mTOR signaling in de novo resistance to BRAF inhibition

Pigment Cell Melanoma Res. 2012 Mar;25(2):248-58. doi: 10.1111/j.1755-148X.2011.00950.x. Epub 2012 Jan 12.

Abstract

BRAF inhibition is highly active in BRAF-mutant melanoma, but the degree and duration of responses is quite variable. Improved understanding of the mechanisms of de novo resistance may lead to rational therapeutic strategies with improved efficacy. Proteomic analysis of BRAF-mutant, PTEN-wild-type human melanoma cell lines treated with PLX4720 demonstrated that sensitive and de novo resistant lines exhibit similar RAS-RAF-MEK-ERK pathway inhibition, but the resistant cells exhibited durable activation of S6 and P70S6K. Treatment with the mTOR inhibitor rapamycin blocked activation of P70S6K and S6, but it also increased activation of AKT and failed to induce cell death. Combined treatment with rapamycin and PX-866, a PI3K inhibitor, blocked the activation of S6 and AKT and resulted in marked cell death when combined with PLX4720. The results support the rationale for combined targeting of BRAF and the PI3K-AKT pathways and illustrate how target selection will be critical to such strategies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Combined Chemotherapy Protocols / pharmacology
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Blotting, Western
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Drug Resistance, Neoplasm* / drug effects
  • Drug Screening Assays, Antitumor
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Gonanes / pharmacology
  • Gonanes / therapeutic use
  • Humans
  • Indoles / pharmacology
  • Indoles / therapeutic use
  • Melanoma / drug therapy
  • Melanoma / enzymology
  • Melanoma / pathology
  • Molecular Targeted Therapy*
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphoinositide-3 Kinase Inhibitors
  • Phosphorylation / drug effects
  • Protein Interaction Maps / drug effects
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Kinase Inhibitors / therapeutic use
  • Proto-Oncogene Proteins B-raf / antagonists & inhibitors*
  • Proto-Oncogene Proteins B-raf / metabolism
  • Signal Transduction* / drug effects
  • Sirolimus / pharmacology
  • Sirolimus / therapeutic use
  • Sulfonamides / pharmacology
  • Sulfonamides / therapeutic use
  • TOR Serine-Threonine Kinases / antagonists & inhibitors
  • TOR Serine-Threonine Kinases / metabolism*

Substances

  • Gonanes
  • Indoles
  • PLX 4720
  • PX-866
  • Phosphoinositide-3 Kinase Inhibitors
  • Protein Kinase Inhibitors
  • Sulfonamides
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf
  • Extracellular Signal-Regulated MAP Kinases
  • Sirolimus