title: Co-targeting ALK and EGFR parallel signaling in oral squamous cell carcinoma.
abstract: Squamous cell carcinoma (SCC) comprises 90% of all head and neck cancers and has a poor survival rate due to late-stage disease that is refractive to traditional therapies. Epidermal growth factor receptor (EGFR) is over-expressed in greater than 80% of head and neck SCC (HNSCC). However, EGFR targeted therapies yielded little to no efficacy in clinical trials. This study investigated the efficacy of co-targeting EGFR and the anaplastic lymphoma kinase (ALK) whose promoter is hypomethylated in late-stage oral SCC (OSCC). We observed increased ALK activity in late-stage human OSCC tumors and invasive OSCC cell lines. We also found that while ALK inhibition alone had little effect on proliferation, co-targeting ALK and EGFR significantly reduced OSCC cell proliferation in vitro. Further analysis showed significant efficacy of combined treatment in HSC3-derived xenografts resulting in a 30% decrease in tumor volumes by 14days (p<0.001). Western blot analysis showed that co-targeting ALK and EGFR significantly reduced EGFR phosphorylation (Y1148) in HSC3 cells but not Cal27 cells. ALK and EGFR downstream signaling interactions are also demonstrated by Western blot analysis in which lone EGFR and ALK inhibitors attenuated AKT activity whereas co-targeting ALK and EGFR completely abolished AKT activation. No effects were observed on ERK1/2 activation. STAT3 activity was significantly induced by lone ALK inhibition in HSC3 cells and to a lower extent in Cal27 cells. Together, these data illustrate that ALK inhibitors enhance anti-tumor activity of EGFR inhibitors in susceptible tumors that display increased ALK expression, most likely through abolition of AKT activation.
authors.affiliation: Cancer Therapy and Research Center, University of Texas Health Science Center at San Antonio (UTHSCSA), San Antonio, TX 78229, USA; Comprehensive Dentistry, UTHSCSA Dental School, San Antonio, TX 78229, USA. Electronic address: gonzalesc5@uthscsa.edu.
authors.forename: Cara B
authors.initials: CB
authors.lastname: Gonzales
authors.affiliation: Comprehensive Dentistry, UTHSCSA Dental School, San Antonio, TX 78229, USA.
authors.forename: Jorge J
authors.initials: JJ
authors.lastname: De La Chapa
authors.affiliation: Pathology, UTHSCSA Medical School, San Antonio, TX 78229, USA.
authors.forename: Pothana
authors.initials: P
authors.lastname: Saikumar
authors.affiliation: Pathology, UTHSCSA Medical School, San Antonio, TX 78229, USA.
authors.forename: Prajjal K
authors.initials: PK
authors.lastname: Singha
authors.affiliation: Pharmacology, UTHSCSA Medical School, San Antonio, TX 78229, USA.
authors.forename: Nicholas F
authors.initials: NF
authors.lastname: Dybdal-Hargreaves
authors.affiliation: Biochemistry, UTHSCSA Medical School, San Antonio, TX 78229, USA.
authors.forename: Jeffery
authors.initials: J
authors.lastname: Chavez
authors.affiliation: Molecular Medicine, UTHSCSA Medical School, San Antonio, TX 78229, USA.
authors.forename: Aaron M
authors.initials: AM
authors.lastname: Horning
authors.affiliation: Pathology, UTHSCSA Medical School, San Antonio, TX 78229, USA.
authors.forename: Jamie
authors.initials: J
authors.lastname: Parra
authors.affiliation: Cancer Therapy and Research Center, University of Texas Health Science Center at San Antonio (UTHSCSA), San Antonio, TX 78229, USA; Molecular Medicine, UTHSCSA Medical School, San Antonio, TX 78229, USA. Electronic address: kirma@uthscsa.edu.
authors.forename: Nameer B
authors.initials: NB
authors.lastname: Kirma
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000378:metabolism*; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D000077156:Gefitinib; D006801:Humans; D008819:Mice, Nude; D009062:Mouth Neoplasms / Q000378:metabolism*; D011799:Quinazolines / Q000494:pharmacology; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D015398:Signal Transduction; D023041:Xenograft Model Antitumor Assays
chemical_list: D011799:Quinazolines; C000626173:ALK protein, human; C000626174:Alk protein, mouse; D000077548:Anaplastic Lymphoma Kinase; C512478:EGFR protein, human; D066246:ErbB Receptors; D020794:Receptor Protein-Tyrosine Kinases; D000077156:Gefitinib
keywords: Anaplastic lymphoma kinase; Epidermal growth factor receptor; Head and neck cancer; Oral squamous cell carcinoma