Journal
CANCER BIOLOGY & THERAPY
Volume 19, Issue 10, Pages 921-933Publisher
TAYLOR & FRANCIS INC
DOI: 10.1080/15384047.2018.1451285
Keywords
ALK; EGFR inhibitor resistance; EGFR; HNSCC; patient-derived models
Categories
Funding
- HHS \ NIH \ National Cancer Institute (NCI) [R01 CA192405, R21 CA180576]
- Oregon Health & Science University, Knight Cancer Institute [P30 CA069533]
- National Center for Advancing Translational Sciences (NCATS) [UL1TR002369]
- NATIONAL CANCER INSTITUTE [R01CA192405, P30CA069533] Funding Source: NIH RePORTER
- NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES [UL1TR002369] Funding Source: NIH RePORTER
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Epidermal growth factor receptor (EGFR) is overexpressed in up to 90% of head and neck squamous cell carcinoma (HNSCC) and associated with poor outcome. An anti-EGFR antibody is the only FDA-approved cancer intrinsic targeted therapy for HNSCC; however, resistance eventually occurs in all patients. In order to extend therapy options, we subjected patient-derived HNSCC cells to small-molecule inhibitor and siRNA screens, to identify effective combination therapies with an EGFR inhibitor, and to repurpose the FDA approved agents for HNSCC. The combinations of EGFR inhibitor with anaplastic lymphoma kinase (ALK) inhibitors were effective in reducing cell viability in 4/8 HNSCC patients' derived tumor cells, and this corresponded with an effectiveness of siRNA targeting ALK combined with the EGFR inhibitor gefitinib. Co-targeting EGFR and ALK decreased HNSCC cell number and colony formation ability and increased annexin V staining. Because ALK expression is low and ALK fusions are infrequent in HNSCC, we hypothesized that gefitinib treatment could induce ALK expression. We show that ALK expression was induced in HNSCC patient-derived cells both in 2D and 3D patient-derived cell culture models, and in patient-derived xenografts. Four different ALK inhibitors, including two (ceritinib and brigatinib) FDA approved for lung cancer, were effective in combination with gefitinib. Together, we identified induction of ALK by EGFR inhibitor as a novel mechanism potentially relevant to resistance to EGFR inhibitor, a high response rate of HNSCC patient-derived tumor cells to a combination of ALK and EGFR inhibitors, and applicability of repurposing ALK inhibitors to HNSCC that lack ALK aberrations.
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