Professor and Chair, Department of Craniofacial Biology
Department of Craniofacial Biology
School of Dental Medicine
Mail Stop 8120, RC1-South, Room L18 11100
12801 E. 17th Ave.
Aurora, CO 80045
Autocrine and paracrine signaling through receptor tyrosine kinases in cancer. Autocrine growth factor signaling, often through receptor tyrosine kinases (RTKs), is a hallmark of cancer cells. Our studies reveal that multiple families of receptor tyrosine kinases engage in autocrine growth stimulation in lung cancer, head and neck cancer and malignant mesothelioma cell lines. Our focus is presently on fibroblast growth factor receptor 1 (FGFR1) as an oncogene driver in these cancers as well as a mechanism of acquired resistance to epidermal growth factor receptor-specific TKIs. Our studies involve functional genomics and pharmacological experiments with cultured cancer cell lines as well as in vivo approaches in immune deficient mice bearing orthotopically implanted cancer cell lines.
Katherine Singleton, Cancer Biology graduate student
Emily Kleczko, Cancer Biology graduate student
Marek, L., Ware, K., Fritzsche, A., Hercule, P., Helton, W.R., Smith, J.E., McDermott, L.A., Coldren, C.D., Nemenoff, R.A., Merrick, D.T., Helfrich, B.A., Bunn, P.A., Jr., and Heasley, L.E. (2009) FGF and FGFR-mediated autocrine signaling in non-small cell lung cancer cells. Mol. Pharmacol., 75:196-207. PMCID: PMC2669785
Kono, S.A., Marshall, M.E., Ware, K.E., and Heasley, L.E. (2009) The fibroblast growth factor receptor signaling pathway as a mediator of intrinsic resistance to EGFR-specific tyrosine kinase inhibitors in non-small cell lung cancer. Drug Resist. Updat. 12:95-102. PMCID: PMC2763047
Ware, K.E., Marshall, M.E., Heasley, L.R., Marek, L., Hinz, T.K., Hercule, P., Helfrich, B.A., and Heasley, L.E. (2010) Rapidly acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in NSCLC cell lines through de-repression of FGFR2 and FGFR3 expression. PLoS ONE, 5(11):e14117. PMCID: PMC2994708
Marshall, M.E., Hinz, T.K., Kono, S.A., Singleton, K.R., Bichon, B., Ware, K.E., Marek, L., Frederick, B.A., Raben, D. and Heasley, L.E. (2011) Fibroblast growth factor receptors are components of autocrine signaling networks in head and neck squamous cell carcinoma cells. Clin. Cancer Res. 17:5016-5025. PMCID: PMC3149730
Doebele, R.C., Pilling, A.B, Aisner, D., Kutateladze, T.G., Le, A.T., Weickhardt, A.J., Kondo, K.L., Linderman, D.J., Heasley, L.E., Franklin, W.A., Vareila-Garcia, M., and Camidge, D.R. (2012) Mechanisms of resistance to Crizotinib in patients with ALK gene rearranged non-small cell lung cancer. Clinical Cancer Res. 18(5):1472-82. PMCID: PMC3311875
Kono SA, Heasley LE, Doebele RC, Camidge DR. (2012) Adding to the mix: Fibroblast growth factor and platelet-derived growth factor receptor pathways as targets in non-small cell lung cancer. Curr Cancer Drug Targets 12:107-23. PMCID in process
Linger, RMA, Cohen, RA, Cummings, CT, Sather, S, Migdall-Wilson, J, Middleton, DHG, Lu, X, Barón, AE, Franklin, WA, Merrick, DT, Jedlicka, P, DeRyckere, D, Heasley, LE, and Graham, DK (2012) Mer or Axl receptor tyrosine kinase inhibition promotes apoptosis, blocks growth, and enhances chemosensitivity of human non-small cell lung cancer. Oncogene, in press.