Reversing melanoma cross-resistance to BRAF and MEK inhibitors by co-targeting the AKT/mTOR pathway

PLoS One. 2011;6(12):e28973. doi: 10.1371/journal.pone.0028973. Epub 2011 Dec 14.

Abstract

Background: The sustained clinical activity of the BRAF inhibitor vemurafenib (PLX4032/RG7204) in patients with BRAF(V600) mutant melanoma is limited primarily by the development of acquired resistance leading to tumor progression. Clinical trials are in progress using MEK inhibitors following disease progression in patients receiving BRAF inhibitors. However, the PI3K/AKT pathway can also induce resistance to the inhibitors of MAPK pathway.

Methodology/principal findings: The sensitivity to vemurafenib or the MEK inhibitor AZD6244 was tested in sensitive and resistant human melanoma cell lines exploring differences in activation-associated phosphorylation levels of major signaling molecules, leading to the testing of co-inhibition of the AKT/mTOR pathway genetically and pharmacologically. There was a high degree of cross-resistance to vemurafenib and AZD6244, except in two vemurafenib-resistant cell lines that acquired a secondary mutation in NRAS. In other cell lines, acquired resistance to both drugs was associated with persistence or increase in activity of AKT pathway. siRNA-mediated gene silencing and combination therapy with an AKT inhibitor or rapamycin partially or completely reversed the resistance.

Conclusions/significance: Primary and acquired resistance to vemurafenib in these in vitro models results in frequent cross resistance to MEK inhibitors, except when the resistance is the result of a secondary NRAS mutation. Resistance to BRAF or MEK inhibitors is associated with the induction or persistence of activity within the AKT pathway in the presence of these drugs. This resistance can be potentially reversed by the combination of a RAF or MEK inhibitor with an AKT or mTOR inhibitor. These combinations should be available for clinical testing in patients progressing on BRAF inhibitors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Benzimidazoles / pharmacology
  • Carrier Proteins / genetics
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm / drug effects*
  • Gene Silencing / drug effects
  • Humans
  • Indoles / pharmacology
  • Inhibitory Concentration 50
  • MAP Kinase Signaling System / drug effects
  • Melanoma / drug therapy
  • Melanoma / enzymology*
  • Melanoma / genetics
  • Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors*
  • Mitogen-Activated Protein Kinase Kinases / metabolism
  • Mutation / genetics
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Kinase Inhibitors / therapeutic use
  • Proto-Oncogene Proteins B-raf / antagonists & inhibitors*
  • Proto-Oncogene Proteins B-raf / metabolism
  • Proto-Oncogene Proteins c-akt / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-akt / metabolism
  • RNA, Small Interfering / metabolism
  • Rapamycin-Insensitive Companion of mTOR Protein
  • Ribosomal Protein S6 Kinases / genetics
  • Sirolimus / pharmacology
  • Sulfonamides / pharmacology
  • TOR Serine-Threonine Kinases / antagonists & inhibitors*
  • TOR Serine-Threonine Kinases / metabolism
  • Vemurafenib

Substances

  • AZD 6244
  • Benzimidazoles
  • Carrier Proteins
  • Indoles
  • Protein Kinase Inhibitors
  • RICTOR protein, human
  • RNA, Small Interfering
  • Rapamycin-Insensitive Companion of mTOR Protein
  • Sulfonamides
  • Vemurafenib
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf
  • Proto-Oncogene Proteins c-akt
  • Ribosomal Protein S6 Kinases
  • Mitogen-Activated Protein Kinase Kinases
  • Sirolimus