Unit: Drug Discovery and Development
Harrison School of Pharmacy
3211g Walker Building
Auburn, AL 36849
Targeted Melanoma Therapy: Identification of ERBB4 Melanoma Driver Mutants
Auburn University Intramural Grants Program
Role: Principal Investigator
Total Cost: $50,000
Overview – We study the Epidermal Growth Factor (EGF) family of peptide hormones and their receptors, the ErbB receptor tyrosine kinases. This network regulates the proliferation and differentiation of epithelial cells and deregulated signaling by this network contributes to human tumorigenesis and increased tumor cell invasiveness, metastatic potential, and chemoresistance. Consequently, we seek to understand the mechanism by which this network regulates cell function, with the ultimate goal being the development of novel cancer treatments.
Mechanisms of ERBB4 signaling – We have demonstrated that ERBB4 homodimers function as tumor suppressor proteins, whereas ERBB4-EGFR and ERBB4-ERBB2 heterodimers function as oncogenes. We are focused on deciphering the mechanisms by which ERBB4 can be coupled to these divergent responses [19, 25, 26, 41, 44, 50, 56]. We are also pursuing the discovery and development of novel ERBB4 agonists and antagonists that can be used to pharmacologically probe ERBB4 function in human malignancies and hold potential for the treatment of ErbB4-dependent tumors [30, 36, 42, 46, 55].
EGF family hormones – We are characterizing the biological activities of EGF family hormones and we are identifying factors that regulate the affinity, potency, and efficacy (intrinsic activity) of these peptide growth factors [20, 23, 24, 29, 30, 32, 34, 36, 40, 42, 45, 46, 51].ERBB4 in human tumors – We have written a comprehensive review of the roles that ERBB4 plays in human tumors . That review has identified several projects underway in our laboratory. Metastatic melanomas that possess wild type (WT) BRAF alleles are particularly deadly, as they do not respond to BRAF inhibitors, MEK inhibitors, or other targeted chemotherapeutics. Our preliminary data indicate that ERBB4 heterodimers function as oncogenes in human melanoma cell lines that possess BRAF WT alleles. We are developing in silico methods to assess whether ERBB4 mutations found in BRAF WT melanoma samples function are likely to function as melanoma drivers. We are utilizing in vitro and in vivo model systems to define the roles of ERBB4 overexpression, ERBB4 heterodimerization partners, ERBB4 ligands, and ERBB4 mutations in BRAF WT human melanoma. Similar but less advanced efforts are underway to determine the role of ERBB4 signaling in human childhood brain tumors and triple negative cancers.
#Indicates a publication that contributes to my Google Scholar i10-Index of 48
*Indicates a publication that contributes to my Google Scholar H-index of 34
#*19. EE Williams, LJ Trout, RM Gallo, SE Pitfield, DJ Penington, I Bryant, and DJ Riese II. A constitutively-active ErbB4 mutant inhibits drug-resistant colony formation by the DU-145 and PC-3 human prostate tumor cell lines. Cancer Lett 192: 67-74 (2003). PMID: 12637154
#20. SS Hobbs, EM Cameron, RP Hammer, ATD Le, RM Gallo, EN Blommel, SL Coffing, and DJ Riese II. Five carboxyl-terminal residues of Neuregulin2 are critical for stimulation of signaling by the ErbB4 receptor tyrosine kinase. Oncogene 23: 883-894 (2004). PMID: 14661053
23. SS Hobbs, RM Gallo, and DJ Riese II. Phe45 of NRG2beta is critical for the affinity of NRG2beta for ErbB4 and for potent stimulation of ErbB4 signaling by NRG2beta. Growth Factors 23: 273-283 (2005). PMID: 16338790
#*24. JL Gilmore, RM Gallo, and DJ Riese II. The EGFR-S442F mutant displays increased affinity for Neuregulin2beta and agonist-independent coupling to downstream signaling events. Biochem J 396: 79-88 (2006). PMID: 16445385
#25. RM Gallo, I Bryant, R Fry, EE Williams, and DJ Riese II. Phosphorylation of ErbB4 on Tyr1056 is critical for inhibition of colony formation by prostate tumor cell lines. Biochem Biophys Res Com 349: 372-382 (2006). PMID: 16934755
#26. SE Pitfield, I Bryant, DJ Penington, G Park, and DJ Riese II. Phosphorylation of ErbB4 on tyrosine 1056 is critical for ErbB4 coupling to inhibition of colony formation by human mammary cell lines. Oncol Res 16: 179-193 (2006). PMID: 17120616
#*29. JL Gilmore, JA Scott, Z Bouizar, A Robling, SE Pitfield, DJ Riese II, and J Foley. Amphiregulin-EGFR signaling regulates PTHrP gene expression in breast cancer cells. Breast Cancer Res Treat 110: 493-505 (2008). PMID: 17882547
#30. KJ Wilson, CP Mill, EM Cameron, SS Hobbs, RP Hammer, and DJ Riese II. Interconversion of Neuregulin2 full and partial agonists for ErbB4. Biochem Biophys Res Com 364: 351-357 (2007). PMID: 17945187
#*36. KJ Wilson, JL Gilmore, J Foley, MA Lemmon, and DJ Riese II. Functional selectivity of EGF Family Peptide Growth Factors: Implications for Cancer. Pharmacol Ther 122: 1-8 (2009). PMID: 19135477
#39. JL Gilmore, RM Gonterman, K Menon, G Lorch, DJ Riese II, A Robling, and J Foley. Reconstitution of amphiregulin-EGFR signaling in lung squamous carcinomas activates PTHrP gene expression and cancer-mediated diseases of the bone. Mol Cancer Res 7: 1714-1728 (2009). PMID: 19825997
#*40. J Foley, NK Nickerson, S Nam, KT Allen, JL Gilmore, KP Nephew, and DJ Riese II. EGFR signaling in breast cancer: Bad to the bone? Sem Cell Dev Biol 21: 951-960 (2010). PMID 20813200
#41. CP Mill, K Gettinger, and DJ Riese II. Ligand stimulation of ErbB4 and a constitutively-active ErbB4 mutant result in different biological responses in human pancreatic tumor cell lines. Exp Cell Res 317: 392-404 (2011). PMID: 21110957
#42. DJ Riese II. Ligand-based receptor tyrosine kinase partial agonists: New paradigm for cancer drug discovery? Expert Opin Drug Disc 6: 185-193 (2011). PMID: 21532939
#*44. CP Mill, MD Zordan, SM Rothenberg, J Settleman, JF Leary, and DJ Riese II. ErbB2 is necessary for ErbB4 ligands to stimulate oncogenic activities in models of human breast cancer. Genes & Cancer 2: 792-804 (2011). PMID: 22393464
#*45. KJ Wilson, CP Mill, S Lambert, J Buchman, TR Wilson, V Hernandez-Gordillo, RM Gallo, Laura MC Ades, J Settleman, and DJ Riese II. EGFR ligands exhibit functional differences in models of paracrine and autocrine signaling. Growth Factors 30: 107-116 (2012). PMID: 22260327
46. KJ Wilson, CP Mill, RM Gallo, EM Cameron, H VanBrocklin, J Settleman, and DJ Riese II. The Q43L mutant of Neuregulin 2beta is a pan-ErbB receptor antagonist. Biochem J 443: 133-144 (2012). PMID: 22216880
#50. RM Gallo, IN Bryant, CP Mill, S Kaverman, and DJ Riese II. Multiple functional motifs are required for the tumor suppressor activity of a constitutively-active ErbB4 mutant. J Cancer Res Ther Oncol 1: 104 (2013). PMID: 24791013
#*51. DJ Riese II and RL Cullum. Epiregulin: Roles in Normal Physiology and Cancer. Sem Cell Dev Biol. 28: 49-56 (2014). PMID 24631357
55. RL Cullum, LM Lucas, JI Senfeld, JT Piazza, LT Neel, K Whig, L Zhai, MH Harris, CC Rael, DC Taylor, LJ Cook, DP Kaufmann, CP Mill, MA Jacobi, FT Smith, M Suto, R Bostwick, RB Gupta, AE David, and DJ Riese II. Development and application of high-throughput screens for the discovery of compounds that disrupt ErbB4 signaling: Candidate cancer therapeutics. PLOS One 15: (12) e0243901 (2020). PMID: 33378376
56. LM Lucas, V Dwivedi, J Senfeld, RL Cullum, CP Mill, JT Piazza, IN Bryant, LJ Cook, ST Miller, C Kelley, E Knerr, J Markham, D Kaufmann, M Jacobi, J Shen, and DJ Riese II. The yin and yang of ERBB4: Tumor suppressor and oncogene. Pharm Rev, accepted (2022).