Ras-induced resistance to lapatinib is overcome by MEK inhibition

G. Zoppoli, E. Moran, D. Soncini, M. Cea, A. Garuti, I. Rocco, G. Cirmena, V. Grillo, L. Bagnasco, G. Icardi, F. Ansaldi, S. Parodi, F. Patrone, A. Ballestrero, A. Nencioni

Research output: Contribution to journalArticle

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 is 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.

Original languageEnglish
Pages (from-to)168-175
Number of pages8
JournalCurrent Cancer Drug Targets
Volume10
Issue number2
DOIs
Publication statusPublished - Mar 2010

Keywords

  • HER2
  • Lapatinib
  • MEK inhibitors
  • Ras

ASJC Scopus subject areas

  • Drug Discovery
  • Pharmacology
  • Cancer Research

Fingerprint Dive into the research topics of 'Ras-induced resistance to lapatinib is overcome by MEK inhibition'. Together they form a unique fingerprint.

  • Cite this

    Zoppoli, G., Moran, E., Soncini, D., Cea, M., Garuti, A., Rocco, I., Cirmena, G., Grillo, V., Bagnasco, L., Icardi, G., Ansaldi, F., Parodi, S., Patrone, F., Ballestrero, A., & Nencioni, A. (2010). Ras-induced resistance to lapatinib is overcome by MEK inhibition. Current Cancer Drug Targets, 10(2), 168-175. https://doi.org/10.2174/156800910791054211