Src and CXCR4 are involved in the invasiveness of breast cancer cells with acquired resistance to lapatinib

Antonella De Luca, Amelia D'Alessio, Marianna Gallo, Monica R. Maiello, Ann M. Bode, Nicola Normanno

Research output: Contribution to journalArticlepeer-review

38 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)148-156
Number of pages9
JournalCell Cycle
Volume13
Issue number1
DOIs
StatePublished - Jan 1 2014

Bibliographical note

Funding Information:
This work was supported by a grant from the Associazione Italiana per la Ricerca sul Cancro (AIRC) to N Normanno (Grant number: IG12118). We thank A Trocino (INT-Fondazione Pascale, Naples, Italy) for bibliographic assistance.

Copyright:
Copyright 2014 Elsevier B.V., All rights reserved.

Keywords

  • Breast cancer
  • CXCR4
  • ErbB-2
  • Lapatinib
  • Resistance
  • Saracatinib
  • Src kinase

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