Ras-Induced Resistance to Lapatinib is Overcome by MEK Inhibition

Author(s): 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.

Journal Name: Current Cancer Drug Targets

Volume 10 , Issue 2 , 2010

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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.

Keywords: Lapatinib, HER2, ras, MEK inhibitors

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Article Details

VOLUME: 10
ISSUE: 2
Year: 2010
Page: [168 - 175]
Pages: 8
DOI: 10.2174/156800910791054211
Price: $58

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