title: Src and CXCR4 are involved in the invasiveness of breast cancer cells with acquired resistance to lapatinib.
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.
authors.affiliation: Cell Biology and Biotherapy Unit; Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale"; IRCCS; Naples, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: De Luca
authors.affiliation: Cell Biology and Biotherapy Unit; Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale"; IRCCS; Naples, Italy.
authors.forename: Amelia
authors.initials: A
authors.lastname: D'Alessio
authors.affiliation: Cell Biology and Biotherapy Unit; Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale"; IRCCS; Naples, Italy.
authors.forename: Marianna
authors.initials: M
authors.lastname: Gallo
authors.affiliation: Cell Biology and Biotherapy Unit; Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale"; IRCCS; Naples, Italy.
authors.forename: Monica R
authors.initials: MR
authors.lastname: Maiello
authors.affiliation: The Hormel Institute; University of Minnesota; Austin, MN USA.
authors.forename: Ann M
authors.initials: AM
authors.lastname: Bode
authors.affiliation: Cell Biology and Biotherapy Unit; Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale"; IRCCS; Naples, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Normanno
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000077341:Lapatinib; D009361:Neoplasm Invasiveness / Q000235:genetics*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011799:Quinazolines / Q000008:administration & dosage*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics; D019718:Receptors, CXCR4 / Q000096:biosynthesis* / Q000378:metabolism; D015398:Signal Transduction; D019061:src-Family Kinases / Q000096:biosynthesis* / Q000378:metabolism
chemical_list: D000077341:Lapatinib; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D019718:Receptors, CXCR4; D019061:src-Family Kinases; C527276:CXCR4 protein, human
keywords: CXCR4; ErbB-2; Src kinase; breast cancer; lapatinib; resistance; saracatinib