title: Identification of anaplastic lymphoma kinase as a potential therapeutic target in Basal Cell Carcinoma.
abstract: The pathogenesis of BCC is associated with sonic hedgehog (SHH) signaling. Vismodegib, a smoothened inhibitor that targets this pathway, is now in clinical use for advanced BCC patients, but its efficacy is limited. Therefore, new therapeutic options for this cancer are required. We studied gene expression profiling of BCC tumour tissues coupled with laser capture microdissection to identify tumour specific receptor tyrosine kinase expression that can be targeted by small molecule inhibitors. We found a >250 fold increase (FDR<10-4) of the oncogene, anaplastic lymphoma kinase (ALK) as well as its ligands, pleiotrophin and midkine in BCC compared to microdissected normal epidermis. qRT-PCR confirmed increased expression of ALK (p<0.05). Stronger expression of phosphorylated ALK in BCC tumour nests than normal skin was observed by immunohistochemistry. Crizotinib, an FDA-approved ALK inhibitor, reduced keratinocyte proliferation in culture, whereas a c-Met inhibitor did not. Crizotinib significantly reduced the expression of GLI1 and CCND2 (members of SHH-pathway) mRNA by approximately 60% and 20%, respectively (p<0.01). Our data suggest that ALK may increase GLI1 expression in parallel with the conventional SHH-pathway and promote keratinocyte proliferation. Hence, an ALK inhibitor alone or in combination with targeting SHH-pathway molecules may be a potential treatment for BCC patients.
authors.affiliation: Laboratory for Investigative Dermatology, The Rockefeller University, New York, NY.
authors.forename: Hanna
authors.initials: H
authors.lastname: Ning
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Mitsui
authors.forename: Claire Q F
authors.initials: CQ
authors.lastname: Wang
authors.forename: Mayte
authors.initials: M
authors.lastname: Suárez-Fariñas
authors.forename: Juana
authors.initials: J
authors.lastname: Gonzalez
authors.forename: Kejal R
authors.initials: KR
authors.lastname: Shah
authors.forename: Jie
authors.initials: J
authors.lastname: Chen
authors.forename: Israel
authors.initials: I
authors.lastname: Coats
authors.forename: Diane
authors.initials: D
authors.lastname: Felsen
authors.forename: John A
authors.initials: JA
authors.lastname: Carucci
authors.forename: James G
authors.initials: JG
authors.lastname: Krueger
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D002280:Basal Cell Carcinoma / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D000077547:Crizotinib; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D061346:Laser Capture Microdissection; D051379:Mice; D008822:Mice, Transgenic; D058990:Molecular Targeted Therapy; D011720:Pyrazoles / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D000071676:Zinc Finger Protein GLI1
chemical_list: C400551:GLI1 protein, human; D053823:Hedgehog Proteins; D011720:Pyrazoles; D011725:Pyridines; D014157:Transcription Factors; D000071676:Zinc Finger Protein GLI1; D000077547:Crizotinib; C000626173:ALK protein, human; C000626174:Alk protein, mouse; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases