The focus of my laboratory centers around the epidermal growth factor receptor (EGFR) which is ubiquitously expressed receptor tyrosine kinase (RTK). Upon ligand binding, the EGFR initiates a spectrum of signaling pathways that promote cell proliferation, differentiation, migration, motility, and cellular adhesion. The EGFR is recognized as a key mediator of proliferation and progression in many human tumors and strategies to inhibit EGFR signaling have emerged as highly promising cancer therapy approaches. Following more than 20 years of preclinical development, five EGFR inhibitors, two monoclonal antibodies and three small molecule tyrosine kinase inhibitors (TKIs), have recently gained FDA approval in oncology (cetuximab, panitumumab, erlotinib, gefitinib and lapatinib). Both strategies of EGFR inhibition have demonstrated major tumor regressions in approximately 10-20% of advanced cancer patients. However, many tumors do not show response to EGFR inhibition and some of the responders eventually manifest resistance to treatment. The underlying mechanisms of intrinsic and acquired resistance to EGFR inhibitors remain largely unexplored. In an effort to examine mechanisms of acquired resistance to EGFR inhibition we have developed a series of cetuximab-resistant cancer cell lines (H&NSCC1 and NCI-H226) models to elucidate molecular pathways leading to resistance to targeted therapies. The overall goal is to elucidate pathways that resistant cells have activated and aim at blocking these pathways and restoring sensitivity to the original target agents.
- Toni M Brand, Mari Iida, Andrew P Stein, Kelsey L Corrigan, Cara M Braverman, John P Coan, Hannah E Pearson, Harsh Bahrar, Tyler L Fowler, Bryan P Bednarz, Sandeep Saha, David Yang, Parkash S Gill, Mark W Lingen, Vassiliki Saloura, Victoria M Villaflor, Ravi Salgia, Randall J Kimple, Deric L Wheeler AXL Is a Logical Molecular Target in Head and Neck Squamous Cell Carcinoma. Clin. Cancer Res.: 2015, 21(11);2601-12 [PubMed:25767293]
Toni M Brand, Mari Iida, Andrew P Stein, Kelsey L Corrigan, Cara M Braverman, Neha Luthar, Mahmoud Toulany, Parkash S Gill, Ravi Salgia, Randall J Kimple, Deric L Wheeler AXL mediates resistance to cetuximab therapy. Cancer Res.: 2014, 74(18);5152-64 [PubMed:25136066]
Toni M Brand, Mari Iida, Emily F Dunn, Neha Luthar, Kellie T Kostopoulos, Kelsey L Corrigan, Matthew J Wleklinski, David Yang, Kari B Wisinski, Ravi Salgia, Deric L Wheeler Nuclear epidermal growth factor receptor is a functional molecular target in triple-negative breast cancer. Mol. Cancer Ther.: 2014, 13(5);1356-68 [PubMed:24634415]
- Mari Iida, Toni M Brand, Megan M Starr, Chunrong Li, Evan J Huppert, Neha Luthar, Mikkel W Pedersen, Ivan D Horak, Michael Kragh, Deric L Wheeler Sym004, a novel EGFR antibody mixture, can overcome acquired resistance to cetuximab. Neoplasia: 2013, 15(10);1196-206 [PubMed:24204198]
- Mari Iida, Toni M Brand, David A Campbell, Chunrong Li, Deric L Wheeler Yes and Lyn play a role in nuclear translocation of the epidermal growth factor receptor. Oncogene: 2013, 32(6);759-67 [PubMed:22430206]