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

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 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

« Previous Next »