TY - JOUR
T1 - Ras-induced resistance to lapatinib is overcome by MEK inhibition
AU - Zoppoli, G.
AU - Moran, E.
AU - Soncini, D.
AU - Cea, M.
AU - Garuti, A.
AU - Rocco, I.
AU - Cirmena, G.
AU - Grillo, V.
AU - Bagnasco, L.
AU - Icardi, G.
AU - Ansaldi, F.
AU - Parodi, S.
AU - Patrone, F.
AU - Ballestrero, A.
AU - Nencioni, A.
PY - 2010/3
Y1 - 2010/3
N2 - 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.
AB - 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.
KW - HER2
KW - Lapatinib
KW - MEK inhibitors
KW - Ras
UR - http://www.scopus.com/inward/record.url?scp=77950640596&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=77950640596&partnerID=8YFLogxK
U2 - 10.2174/156800910791054211
DO - 10.2174/156800910791054211
M3 - Article
C2 - 20088787
AN - SCOPUS:77950640596
VL - 10
SP - 168
EP - 175
JO - Current Cancer Drug Targets
JF - Current Cancer Drug Targets
SN - 1568-0096
IS - 2
ER -