Co-targeting ALK and EGFR parallel signaling in oral squamous cell carcinoma. (August 2016)

• Record Type: Journal Article
• Authors: Gonzales, Cara B.; De La Chapa, Jorge J.; Saikumar, Pothana; Singha, Prajjal K.; Dybdal-Hargreaves, Nicholas F.; Chavez, Jeffery; Horning, Aaron M.; Parra, Jamie; Kirma, Nameer B.
• Is Part Of: Oral oncology. Volume 59(2016:Aug.)
• Page Start: 12
• Page End: 19
• Publication Date: 2016-08
• Subjects: Anaplastic lymphoma kinase -- Epidermal growth factor receptor -- Oral squamous cell carcinoma -- Head and neck cancer; anaplastic lymphoma kinase (ALK) -- epidermal growth factor receptor (EGFR) -- oral squamous cell carcinoma (OSCC); Mouth -- Cancer -- Periodicals; Mouth -- Tumors -- Periodicals; Mouth Diseases -- Periodicals; Mouth Neoplasms -- Periodicals; Bouche -- Cancer -- Périodiques; Bouche -- Tumeurs -- Périodiques; Tumeurs -- Périodiques; Electronic journals; 616.9943105
• DOI: 10.1016/j.oraloncology.2016.05.007
• Languages: English
• ISSNs: 1368-8375

Abstract

Highlights: Late-stage OSCC express high levels of activated ALK protein compared to early-stage tumors. Gefitinib reduces invasive HSC3 tumor growth in vivo . Co-targeting ALK and EGFR additively and significantly reduces HSC3 tumor growth. Co-treating OSCC cells with ALK inhibitor (TAE684) and EGFR inhibitor (Gefitinib) abolishes AKT activation. TAE684 up-regulates p-STAT3 in OSCC cell lines. Summary: 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 14 days ( 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.