Craniofacial Biology
Mail Stop 8120, RC1-S, Rm L18 11102
12801 E. 17th Ave.
Aurora, CO 80045
Phone: 303-724-4578
Fax: 303-724-4580
Email: Lynn.Heasley@ucdenver.edu
Education:
- PhD (Pharmacology), University of California at San Diego
Postdoctoral Training:
- Department of Biochemistry, University of Massachusetts Medical Center, Worcester, MA
- Division Basic Sciences, National Jewish Center for Immunology and Respiratory Medicine, Denver, CO
Departmental Affiliations:
- Craniofacial Biology, School of Dental Medicine
- Department of Pharmacology, School of Medicine
Graduate Program Affiliations:
- Biomedical Sciences Program (BSP)
- Medical Scientist Training Program (MSTP)
- Pharmacology
- Cancer Biology Program
Research Interests:
Autocrine and paracrine signaling through polypeptide growth factors in cancer. Autocrine growth factor signaling, often through receptor tyrosine kinases (RTKs), is a hallmark of cancer cells. While EGF receptors (EGFRs) and the EGF family of ligands were thought to constitute a dominant autocrine pathway in human non-small cell lung cancer (NSCLC) and head and neck squamous cell carcinoma (HNSCC), only a fraction of the patients exhibit a clinical response to the EGFR tyrosine kinase inhibitors (TKI), gefitinib and erlotinib. Thus, consistent with the known heterogeneity of NSCLC, EGFR is not the only RTK mediating autocrine growth in lung cancer. Importantly, we have recently found that fibroblast growth factor 2 (FGF2), FGF9 and FGF receptors (FGFRs) are frequently co-expressed in NSCLC and HNSCC cell lines. Moreover, FGF2 shRNAs, dominant-negative FGFR1 and FGFR-selective TKIs (RO4383596, AZ12908010) selectively reduce growth of NSCLC or HNSCC cell lines that co-express FGF2 or FGF9 and FGFRs. By contrast, cell lines lacking FGF2 expression are resistant to RO4383596 and sensitive to gefitinib. We are also actively exploring mechanisms of resistance, both acquired and intrinsic, to different TKIs. Interestingly, treatment of EGFR dominant NSCLC and HNSCC cell lines with EGFR-specific TKIs results in transcriptional induction of FGFR2 and FGFR3 as well as the cytokine, TGFb2. We are actively pursuing these as novel acquired resistance mechanisms. Finally, we have recently initiated synthetic lethal screens with distinct NSCLC and HNSCC cell lines and FGFR-specific TKIs to identify novel pathways that can be targeted with combined therapeutics to enhance the efficacy of TKIs in these cancers.
Selected Publications:
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.
Wang, X.Q., Li, H., Van Putten, V., Winn, R.A., Heasley, L.E., and Nemenoff, R.A. (2009) Oncogenic K-Ras regulates proliferation and cell junctions in lung epithelial cells through induction of COX-2 and activation of MMP9. Mol. Biol. Cell. 20:791-800.
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.
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, in press.
Marshall, M.E., Hinz, T.K., Ware, K.E., Kono, S., Marek, L., Bichon, B., Frederick, B.A. Raben D., and Heasley, L.E. Fibroblast growth factor (FGF) and FGF receptor autocrine signaling in EGFR-resistant head and neck squamous cell carcinoma cells. Manuscript submitted.