Oncotarget

Research Papers:

Identification of anaplastic lymphoma kinase as a potential therapeutic target in Basal Cell Carcinoma

Hanna Ning, Hiroshi Mitsui _, Claire Q.F. Wang, Mayte Suárez-Fariñas, Juana Gonzalez, Kejal R. Shah, Jie Chen, Israel Coats, Diane Felsen, John A. Carucci and James G. Krueger

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Oncotarget. 2014; 4:2237-2248. https://doi.org/10.18632/oncotarget.1357

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Abstract

Hanna Ning1,*, Hiroshi Mitsui1,*, Claire Q.F. Wang1, Mayte Suárez-Fariñas1,2, Juana Gonzalez1,2, Kejal R. Shah3, Jie Chen4, Israel Coats1, Diane Felsen4, John A. Carucci5, and James G. Krueger1

1 Laboratory for Investigative Dermatology, The Rockefeller University, New York, NY

2 Center for Clinical and Translational Science, The Rockefeller University, New York, New York, USA

3 Texas Dermatology Associates, Baylor University Medical Center, Dallas, TX USA

4 Institute for Pediatric Urology, Department of Urology, Weill Cornell Medical College, New York, NY

5 Ronald O. Perelman Department of Dermatology, New York University Langone Medical Center, New York, NY

* These two authors contributed equally to this manuscript.

Correspondence:

James G. Krueger, email:

Keywords: Basal cell carcinoma, oncogenic kinases, cancer, therapy

Received: September 1, 2013 Accepted: September 30, 2013 Published: October 2, 2013

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.


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