title: Anti-invasion, anti-proliferation and anoikis-sensitization activities of lapatinib in nasopharyngeal carcinoma cells.
abstract: Nasopharyngeal cancer (NPC) is a highly prevalent and invasive head and neck cancer in Asia. Disease recurrence and distant metastasis account for major NPC deaths. Therefore, more effective therapy is needed. Lapatinib, a dual tyrosine kinase inhibitor (TKI) against both EGFR and HER-2, has been known to exert potent antitumor activity against several cancer models. Given that both EGFR and HER-2 are co-expressed in NPC, we hypothesized that dual targeting of EGFR and HER-2 by this small molecule EGFR/HER-2 TKI would elicit anti-tumor activity in NPC. Using in vitro models of NPC, we demonstrated that lapatinib was able to efficiently inhibit the phosphorylation of both EGFR and HER-2. This was accompanied by significant growth inhibition of NPC cells (with maximal growth inhibition >90%). For the most lapatinib-sensitive cell line (HK1-LMP1, with IC(50) ∼ 600 nM), which harbored the highest levels of both EGFR and HER-2, inhibition of cell growth was associated G(0)/G(1) cell cycle arrest, marked PARP cleavage, caspase-3 cleavage, as well as significant downregulation of several important survival proteins (e.g. survivin, Mcl-1 and cyclin D1). NPC cells are intrinsically invasive. We found that lapatinib was able to inhibit cellular invasion of both HK1-LMP1 and HONE-1 cells. Furthermore, our data demonstrated for the first time that lapatinib harbored potent anoikis-sensitization activity (i.e. sensitizing cancer cells to detachment-induced apoptosis) in human cancer cells overexpressing both EGFR and HER-2 (HK1-LMP1 and HK1). Taken together, our findings suggest that lapatinib is a promising anti-cancer agent for NPC with anti-invasion and anoikis-sensitization activities.
authors.affiliation: Department of Clinical Oncology, Chinese University of Hong Kong, Hong Kong, SAR, Hong Kong. vivian@clo.cuhk.edu.hk
authors.forename: Vivian Wai Yan
authors.initials: VW
authors.lastname: Lui
authors.forename: Cecilia Pik Yuk
authors.initials: CP
authors.lastname: Lau
authors.forename: Kakiu
authors.initials: K
authors.lastname: Ho
authors.forename: Margaret Heung Ling
authors.initials: MH
authors.lastname: Ng
authors.forename: Suk Hang
authors.initials: SH
authors.lastname: Cheng
authors.forename: Sai-Wah
authors.initials: SW
authors.lastname: Tsao
authors.forename: Chi Man
authors.initials: CM
authors.lastname: Tsang
authors.forename: Kenny Ieng Kit
authors.initials: KI
authors.lastname: Lei
authors.forename: Anthony Tc
authors.initials: AT
authors.lastname: Chan
authors.forename: Tony Shu Kam
authors.initials: TS
authors.lastname: Mok
mesh_terms: D023102:Anoikis; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002277:Carcinoma; D053148:Caspase 3 / Q000187:drug effects / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D006801:Humans; D000077341:Lapatinib; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D009361:Neoplasm Invasiveness / Q000517:prevention & control; D011065:Poly(ADP-ribose) Polymerases / Q000187:drug effects / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors
chemical_list: D000970:Antineoplastic Agents; D053148:Caspase 3; D066246:ErbB Receptors; D000077341:Lapatinib; D011065:Poly(ADP-ribose) Polymerases; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human