title: Positive interaction between lapatinib and capecitabine in human breast cancer models: study of molecular determinants.
abstract: The combination of lapatinib and capecitabine is approved in Her2+ metastatic breast cancer. However, the pharmacological mechanisms for this association have not been fully elucidated. In this non-clinical study, we evaluated the efficacy of this association on a panel of six human breast cancer cell lines as a means to identify the molecular determinants of response to this combination. Cell viability was evaluated after concomitant/sequential exposure, and response/resistance determinants for each drug such as dihydropyrimidine dehydrogenase (DPD), thymidylate synthase (TS), thymidine phosphorylase, Bax, Bcl2, P21 levels, and phospho p42/44 and HER1/2 signaling pathway were studied. Lapatinib proved to markedly downregulate TS activity, thus suggesting a subsequent better efficacy of capecitabine. Capecitabine optimized the downregulation of p-AKT and p-P42/44 expression by lapatinib. Consequently, we observed an increase in the Bax/Bcl2 ratio and p21 protein expression in cells exposed to the combination. Overall, our data showed that whatever the schedule and the cell line were, additive to synergistic interaction was achieved in our models. The optimal in vitro combination was finally tested in tumor-bearing mice. Our results fully confirmed that associating both drugs led to a 77% reduction in tumor growth as compared with control animals in BT474-xenografted models. Taken together, this non-clinical study shows that lapatinib and capecitabine modulate each other's molecular determinants of response and that concomitant dosing seems to be the optimal way to combine these drugs. Besides, modulation of TS expression by lapatinib makes its association with capecitabine a promising way to overcome breast cancers resistant in relation with TS overexpression.
authors.affiliation: Oncopharmacology Unit, Centre Antoine Lacassagne, 06189 Nice, France.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Chefrour
authors.forename: Gérard
authors.initials: G
authors.lastname: Milano
authors.forename: Patricia
authors.initials: P
authors.lastname: Formento
authors.forename: Sarah
authors.initials: S
authors.lastname: Giacometti
authors.forename: Amine
authors.initials: A
authors.lastname: Denden
authors.forename: Nicole
authors.initials: N
authors.lastname: Renée
authors.forename: Athanassios
authors.initials: A
authors.lastname: Iliadis
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Fischel
authors.forename: Joseph
authors.initials: J
authors.lastname: Ciccolini
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D000069287:Capecitabine; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004357:Drug Synergism; D004815:Epidermal Growth Factor / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D000077341:Lapatinib; D051379:Mice; D008819:Mice, Nude; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011799:Quinazolines / Q000008:administration & dosage / Q000494:pharmacology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013939:Thymidine Phosphorylase / Q000378:metabolism; D013940:Thymidylate Synthase / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000069287:Capecitabine; D018797:Cell Cycle Proteins; D003841:Deoxycytidine; D042943:Dihydrouracil Dehydrogenase (NADP); D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D005472:Fluorouracil; D000077341:Lapatinib; D020928:Mitogen-Activated Protein Kinases; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D013939:Thymidine Phosphorylase; D013940:Thymidylate Synthase; C512478:EGFR protein, human; C508053:ERBB2 protein, human