| Autor: |
De Luca A; Cell Biology and Biotherapy Unit; Istituto Nazionale per lo Studio e la Cura dei Tumori 'Fondazione Giovanni Pascale'; IRCCS; Naples, Italy., D'Alessio A; Cell Biology and Biotherapy Unit; Istituto Nazionale per lo Studio e la Cura dei Tumori 'Fondazione Giovanni Pascale'; IRCCS; Naples, Italy., Gallo M; Cell Biology and Biotherapy Unit; Istituto Nazionale per lo Studio e la Cura dei Tumori 'Fondazione Giovanni Pascale'; IRCCS; Naples, Italy., Maiello MR; Cell Biology and Biotherapy Unit; Istituto Nazionale per lo Studio e la Cura dei Tumori 'Fondazione Giovanni Pascale'; IRCCS; Naples, Italy., Bode AM; The Hormel Institute; University of Minnesota; Austin, MN USA., Normanno N; Cell Biology and Biotherapy Unit; Istituto Nazionale per lo Studio e la Cura dei Tumori 'Fondazione Giovanni Pascale'; IRCCS; Naples, Italy. |
| Jazyk: |
angličtina |
| Zdroj: |
Cell cycle (Georgetown, Tex.) [Cell Cycle] 2014; Vol. 13 (1), pp. 148-56. Date of Electronic Publication: 2013 Oct 29. |
| DOI: |
10.4161/cc.26899 |
| Abstrakt: |
Lapatinib is a dual EGFR and ErbB-2 tyrosine kinase inhibitor that has significantly improved the clinical outcome of ErbB-2-overexpressing breast cancer patients. However, patients inexorably develop mechanisms of resistance that limit the efficacy of the drug. In order to identify potential targets for therapeutic intervention in lapatinib-resistant patients, we isolated, from ErbB-2-overexpressing SK-Br-3 breast cancer cells, the SK-Br-3 Lap-R-resistant subclone, which is able to routinely grow in 1 µM lapatinib. Resistant cells have a more aggressive phenotype compared with parental cells, as they show a higher ability to invade through a matrigel-coated membrane. Lapatinib-resistant cells have an increased Src kinase activity and persistent levels of activation of ERK1/2 and AKT compared with parental cells. Treatment with the Src inhibitor saracatinib in combination with lapatinib reduces AKT and ERK1/2 phosphorylation and restores the sensitivity of resistant cells to lapatinib. SK-Br-3 Lap-R cells also show levels of expression of CXCR4 that are higher compared with parental cells and are not affected by Src inhibition. Treatment with saracatinib or a specific CXCR4 antibody reduces the invasive ability of SK-Br-3 Lap-R cells, with the two drugs showing cooperative effects. Finally, blockade of Src signaling significantly increases TRAIL-induced cell death in SK-Br-3 Lap-R cells. Taken together, our results demonstrate that breast cancer cells with acquired resistance to lapatinib have a more aggressive phenotype compared with their parental counterpart, and that Src signaling and CXCR4 play an important role in this phenomenon, thus representing potential targets for therapeutic intervention in lapatinib-resistant breast cancer patients. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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