Ras-induced resistance to lapatinib is overcome by MEK inhibition

Curr Cancer Drug Targets. 2010 Mar;10(2):168-75. doi: 10.2174/156800910791054211.

Abstract

Lapatinib, a dual HER2 and EGFR tyrosine kinase inhibitor is highly active in HER2+ breast cancer. However, its efficacy is limited by either primary or acquired resistance. Although mutations in ras genes are rarely found in breast cancer, H-ras overexpression is frequently observed. Moreover, genetic alterations that do not directly involve ras such as Brk amplification, ultimately result in increased ras signaling. Using SKBR3 cells, a HER2+ breast cancer cell line that is naturally devoid of mutations in PI3KCA, PTEN, BRAF, and ras we show that both H-ras overexpression and expression of an oncogenic ras allele (ras V12) reduce susceptibility to lapatinib in analogy to what observed with activating PI3KCA mutations and with a constitutively active form of Akt. Importantly, we found that resistance to lapatinib due to ras overexpression or to ras V12 is overcome by MEK inhibition with U0126, suggesting a key role for the MEK-Erk pathway in ras-induced resistance. Similar results were obtained in BT474 cells, another HER+ breast cancer cell line. Therefore, our data indicate that overexpressed/mutated ras may act as a biological modifier of the response to lapatinib. Combining MEK inhibitors with lapatinib may help overcome this form of resistance and increase the efficacy of lapatinib in these tumors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / genetics
  • Breast Neoplasms / pathology
  • Butadienes / pharmacology
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Cell Transformation, Neoplastic / drug effects
  • Drug Resistance, Neoplasm*
  • Enzyme Inhibitors / pharmacology
  • Female
  • Genes, ras / drug effects*
  • Genes, ras / physiology
  • Humans
  • Immunoblotting
  • Lapatinib
  • Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors*
  • Mitogen-Activated Protein Kinase Kinases / genetics
  • Mitogen-Activated Protein Kinase Kinases / metabolism
  • Mutation / genetics
  • Nitriles / pharmacology
  • Quinazolines / pharmacology*
  • Receptor, ErbB-2 / metabolism
  • Signal Transduction

Substances

  • Antineoplastic Agents
  • Butadienes
  • Enzyme Inhibitors
  • Nitriles
  • Quinazolines
  • U 0126
  • Lapatinib
  • ERBB2 protein, human
  • Receptor, ErbB-2
  • Mitogen-Activated Protein Kinase Kinases