Ras-induced resistance to lapatinib is overcome by MEK inhibition.

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.

• Authors: Gabriele Zoppoli, Eva Moran, Debora Soncini, Michele Cea, Anna Garuti, Ilaria Rocco, Gabriella Cirmena, Valentina Grillo, Luca Bagnasco, Giancarlo Icardi, Filippo Ansaldi, Silvio Parodi, Franco Patrone, Alberto Ballestrero, Alessio Nencioni
• Journal: Current cancer drug targets (Curr Cancer Drug Targets) Vol. 10 Issue 2 Pg. 168-75 (Mar 2010) ISSN: 1873-5576 [Electronic] Netherlands
• PMID: 20088787 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

• Antineoplastic Agents (pharmacology)
• Breast Neoplasms (drug therapy, genetics, 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, physiology)
• Humans
• Immunoblotting
• Lapatinib
• Mitogen-Activated Protein Kinase Kinases (antagonists & inhibitors, genetics, metabolism)
• Mutation (genetics)
• Nitriles (pharmacology)
• Quinazolines (pharmacology)
• Receptor, ErbB-2 (metabolism)
• Signal Transduction