Epidermal Growth Factor Signaling Pathway. R. Armijo, D. Dinh, S. Hindi, S. Jehle, J. Jones & L. Lawson

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1 Epidermal Growth Factor Signaling Pathway R. Armijo, D. Dinh, S. Hindi, S. Jehle, J. Jones & L. Lawson

2 Overview of the EGF Pathway AK LECTURES. EGF Signal Transduction Pathway. Accessed October 10,

3 Overview of the EGF Pathway These are members of the RTK family of proteins Comprised of 4 receptors 1. EGFR (ErbB-1/HER1) 2. ErbB-2 (Neu, HER2) 3. ErbB-3 (HER3) 4. ErbB-4 (HER4) Activated by growth factors or EGF-family characterized by 3 disulfide-bonds ( EGF/EGFR signaling pathway, n.d.)

4 ErbB3/HER3 Receptor Ligand: NRG-1 and NRG-2 Elevated expression of HER3 is frequently observed in various malignancies, where it seems to promotes tumor progression via interactions with other receptor tyrosine kinases (RTKs)

5 Overview of Erb2/HER2 Pathway Constitutively exists in the activated state. Overexpression of HER2 occurs in 15-30% of breast and ovarian cancer. Resulting in up to 2 million receptors expressed on the tumor cell surface. Heterodimerize and Homodimerize. (Moasser, M et al. 2007)

Overview of Erb3/HER3 Pathway Impaired kinase function remains in inactive state Neuregulin-1 (NRG1) = HER3 ligand Heterodimerization with HER2 Activation of PI3K/AKT Pathway

6 Overview of Erb3/HER3 Pathway Impaired kinase function remains in inactive state Neuregulin-1 (NRG1) = HER3 ligand Heterodimerization with HER2 Activation of PI3K/AKT Pathway 50-70% of human breast cancer tissue has elevated HER3 expression Can also cause cancer in ovaries, colon, prostate, pancreas, stomach, oral cavity, and lungs. (Gala, K. et al 2014)

7 Regulation of ErbB3/HER3 Activity is resistant to HER2 targeting tyrosine kinase inhibitors in breast cancer. Interacting proteins such as E3 ubiquitin ligase NEDD4, Nrdp1 and Nrdp1 regulator USP 8. MicroRNAs such as mir205, mir125a and mir125b Studies have shown that both HER2 and HER3 antibodies prevent heterodimerization (Mujoo, K.et al 2014)

8 Clinical Implications of HER2/HER3 Overexpression leads to cancer Different types of cancers create challenges in treatment The complexities of pathways are still not fully understood

Survival Rates Stage 0: Cancer is limited to the inside of the milk duct and is a non-invasive cancer Stage 1: Small and either have not spread to the lymph nodes or have only a tiny area of cancer

9 Survival Rates Stage 0: Cancer is limited to the inside of the milk duct and is a non-invasive cancer Stage 1: Small and either have not spread to the lymph nodes or have only a tiny area of cancer spread in the sentinel lymph node State 2: These breast cancers are larger than stage I cancers and/or have spread to a few nearby lymph nodes. Stage 3: These tumors are larger or are growing into nearby tissues (the skin over the breast or the muscle underneath), or they have spread to many nearby lymph nodes. Stage 4: Cancer has spread beyond the breast and nearby lymph nodes to other parts of the body. ( ER-Positive Breast Cancer, 2018)

10 Cancer Treatment ER/PR options Anti-estrogen Aromatase inhibitors

11 Cancer Treatment HER2+ options Herceptin (trastuzumab) Anti-HER2 monoclonal antibody Perjeta (pertuzumab) HER2-directed humanized monoclonal antibody. HER2 Dimerisation Inhibitor (HDI) Binds to domain 2 and blocks ligand activated pairing of HER2 with other HER family members like HER3

12 Challenges to Treatment

13 ( Triple-negative Breast Cancer, 2017) Challenges to Treatment

14 Where is the Research Going (Osada et al., 2018) (Lyu, Han, Polsdofer, Liu, & Liu, 2018)

15 Conclusion HER2 and HER3 HER2 and HER3 antibodies Furture exporlation of EGF Pathway HER2 HER3

16 References AK LECTURES. (n.d.). EGF Signal Transduction Pathway. Retrieved from EGF/EGFR signaling pathway. (n.d.). Retrieved October 10, 2018, from ER-Positive Breast Cancer: Prognosis, Life Expectancy, and More. (2018, September 6). Retrieved October 10, 2018, from Gala, K., and S. Chandarlapaty. Molecular Pathways: HER3 Targeted Therapy. Clinical Cancer Research, vol. 20, no. 6, Nov. 2014, pp , doi: / ccr Lyu, H., Han, A., Polsdofer, E., Liu, S., & Liu, B. (2018). Understanding the biology of HER3 receptor as a therapeutic target in human cancer. Acta Pharmaceutica Sinica B, 8(4), Lyu, H., Huang, J., Edgerton, S. M., Thor, A. D., He, Z., & Liu, B. (2015). Increased erbb3 promotes erbb2/neu-driven mammary tumor proliferation and co-targeting of erbb2/erbb3 receptors exhibits potent inhibitory effects on breast cancer cells. International Journal of Clinical and Experimental Pathology, 8(6), Ma, J., Lyu, H., Huang, J., & Liu, B. (2014). Targeting of erbb3 receptor to overcome resistance in cancer treatment. Molecular Cancer, 13,

17 Moasser, M M. The Oncogene HER2: Its Signaling and Transforming Functions and Its Role in Human Cancer Pathogenesis. Oncogene, vol. 26, no. 45, 2007, pp , doi: /sj.onc Mujoo, K., Choi, B.-K., Huang, Z., Zhang, N., & An, Z. (2014a). Regulation of ERBB3/HER3 signaling in cancer. Oncotarget, 5(21), Osada, T., Hartman, Z. C., Wei, J., Lei, G., Hobeika, A. C., Gwin, W. R., Lyerly, H. K. (2018). Polyfunctional anti-human epidermal growth factor receptor 3 (anti-her3) antibodies induced by HER3 vaccines have multiple mechanisms of antitumor activity against therapy resistant and triple negative breast cancers. Breast Cancer Research, 20(1). Osborne, C. K., Hamilton, B., Titus, G., & Livingston, R. B. (1980). Epidermal Growth Factor Stimulation of Human Breast Cancer Cells in Culture, 40, 7. Singh, B., Carpenter, G., & Coffey, R. J. (2016). EGF receptor ligands: recent advances. F1000Research, 5. Triple-negative Breast Cancer: What You Should Know. (2017, March 3). Retrieved October 10, 2018, fromhttps://

7/6/2015. Cancer Related Deaths: United States. Management of NSCLC TODAY. Emerging mutations as predictive biomarkers in lung cancer: Overview

7/6/2015. Cancer Related Deaths: United States. Management of NSCLC TODAY. Emerging mutations as predictive biomarkers in lung cancer: Overview Emerging mutations as predictive biomarkers in lung cancer: Overview Kirtee Raparia, MD Assistant Professor of Pathology Cancer Related Deaths: United States Men Lung and bronchus 28% Prostate 10% Colon