1. Epidermal Growth Factor Receptors (ErbB-1) and it’s role in Cancer By Jeron Fleming Photo retrieved from http://sec4.edublogs.org/files/2010/06/Cancer_Biology.jpg

2. Introduction Cancer involves uncontrolled growth of cells often leading to malignant tumors which may travel throughout the body In breast, bladder, cervix, kidney, and ovarian tumors, as well as some lung cancer and various squamous carcinomas, overexpression of a mutated EGFR is frequently observed. (Voldborg, B. et al. 1997) The specific causes of cancer are unknown, as many environmental factors can lead to cancer, such as tobacco use, diet (fried foods, red meats), alcohol, sun exposure, infections, stress, obesity, physical inactivity, and environmental pollution (Anand P. et al. 2008). Only 5-10% of cases are due to genetic defect (Anand, P. et al. 2008). Image retrieved from http://www.surgical notes.co.uk/?q=nod e/369

3. Introduction Most common found mutant of EGFR in human cancer is EGFRvIII, being seen in more than 50% of high and low grade gliomas, in 5 of 32 lung carcinomas, in 21 of 27 breast carcinomas, in 4 of 6 pediatric gliomas, in 6 of 7 medulloblastomas, and in 24 of 32 ovarian carcinomas (Voldborg, B. et al. 1997). An intragene rearrangement occurs, resulting in overexpression of transcripts lacking exons. Results in a truncated EGFR that remains constitutively active (continues to send signal to Ras pathway) and no longer binds ligands. May also arise from alternative splicing (Voldborg, B. et al. 1997) Also, internalisation and degradation by the cell become impossible, leading to increased proliferation and tumorigenicity (Voldborg, B. et al. 1997) EGFRvIII mutants do not autophosporylate as well as wildtype EGFR, thus it is less activated than normal EGFR and must be overexpressed by cancer cells to be useful Photo retrieved from (Voldborg, B. et al. 1997)

4. Introduction Mutations in the Tyrosine kinase domain of the protein are also observed, resulting in more intracellular downstream signaling (http://Egfr- info.co.uk, 2013) Development of malignant phenotype may also result from overexpression of EGFR or its ligands, and from coexpression of ligands and receptor (Voldborg, B. et al. 1997) Image retrieved from http://www.discoverymedicine.com/ Nirit-Yarom/2011/02/05/the-role-of- the-epidermal-growth-factor- receptor-in-the-mechanism-and- treatment-of-colorectal-cancer/

5. Brief History EGF first discovered by Stanley Cohen in 1962, using salivary gland extracts. 10 years later, it’s receptor is discovered by Hollenberg and Pedro using cultured cells that responded to EGF mitogenic signal (http://discoverymedicine.com, 2011) In 1988, Aboud-Pirak, et al. concluded that tumor cells are dependent on these receptors activity to a certain extent, suggesting inhibition of the pathway as means of treating the condition (http://discoverymedicine.com, 2011) Stimulation of EGFR pathways is shown to increase tumor cell motility, adhesion, and metastasis by Engebraaten et al. (http://discoverymedicine.com, 2011) Each year, 12.7 million people are diagnosed with cancer, and 7.6 million people die from cancer worldwide. (http://cdc.gov, 2011). Life expectancy and severity of illness rely on progress of the illness at time of diagnosis. The earlier treatment regimens are initiated, the greater chance of survival. Recurrence of the disease is possible and happens often Photo retrieved from https://www.tracy.k12.ca.us/sites /jrio/Pages/WorldHistory.aspx

6. Symptoms and Complications The most common complications include depression, fatigue, metastasis and pain. Most often fatal if untreated or treatment is initiated late into the condition (http://topics.info, 2013). Those diagnosed with cancer are at greater risk of developing mood disorders, and are 2 to 10 times more likely to commit suicide compared to the general pop. (http://topics.info, 2013). Growth of tumors can push on surrounding organs and tissues causing pain, either visceral (damaged organ tissue), somatic (affecting a specific area of the muscle, bone or skin), or neuropathic (damage to the CNS) Survival rate decreased when ErbB1 (EGFR) is overexpressed (Fujiwara, S. et al., 2012). Metastasis is the worst complication, as it spreads to other vital that haven’t become malignant, making isolation and removal of a growth very difficult. This greatly decreases survival rate Photo retrieved from http://upload.wikimedia.org/wikipedia/commons/9/93/Symptoms_of_cancer_met astasis.png

7. Testing for the Mutation and Treatment The EGFR gene is analyzed for mutations at exons 18-21 by obtaining a sample of the tumor from the patient during biopsy. A pathologist performs detection methods for the gene mutation using PCR, sequencing, or ARMS (amplification refractory mutation system) (http://egfr-info.co.uk, 2013) EGFR targeted treatment is only successful in some cancers, mostly colon cancer, but may prove effective when coupled with chemotherapy (http://cepmed.dnadirect.com, 2013). Monoclonal antibodies have been developed to either prevent binding of the ligand to the extracellular domain, or inhibit the Tyrosine Kinase domain of the protein, inhibiting the autophosporylation and downstream intracellular signaling (Ciardiello, F. and Tortora, G., 2001). Some inhibitors include Inhibitors also stop the continous signal of growth, possibly leading to cell death and cessation of tumor metastasis (http://cepmed.dnadirect.com. 2013) cetuximab (Erbitux®) or panitumumab (Vectibix®)

8. Recent Research: Abundance of Mutated EGFR May Predict Benefits of Tyrosine Kinase Inhibitor Treatment Patients were diagnosed to have high abundance of EGFR mutation, low abundance, or wild type EGFR, and are then treated with the TKI gefitinib It was observed that progression-free survival was significantly larger in patients with a low abundance of mutation compared to those with wild type receptors (2.1 mos in wt compared to 6.9 mos in mutated.) Overall survival rate nearly doubled in time when high abundance mutation patients were compared to wild type carriers (15.9 mos in high abundance carriers compared to 8.7 mos in wt carriers) Conducted by Zhou, Q., et al., 2011

9. References Anand, P. et al. (2008). Cancer is a Preventable Disease that Requires Major Lifestyle Changes. Pharm Res., 25 (9), pp.2097-2116. Cdc.gov (2011). CDC Features - World Cancer Day. [online] Retrieved from: http://www.cdc.gov/features/worldcancerday/ [Accessed: 15 Apr 2013]. Cepmed.dnadirect.com (2013). Cepmed - Promoting the Practice and Science of Personalized Medicine - EGFR, Cancer, and Targeted Therapy. [online] Retrieved from: https://cepmed.dnadirect.com/grc/patient-site/kras/egfr-cancer-and-targeted- therapy.html?z4l9r7XepRg9JPjhxxgDzSa [Accessed: 15 Apr 2013]. Ciardiello, F. and Tortora, G. (2001). A novel approach in the treatment of cancer: targeting the epidermal growth factor receptor.. Clinical cancer research : an official journal of the American Association for Cancer Research, 7 (10), pp.2958-2970. Discoverymedicine.com (2011). The Role of the Epidermal Growth Factor Receptor in the Mechanism and Treatment of Colorectal Cancer - Nirit Yarom - Discovery Medicine. [online] Retrieved from: http://www.discoverymedicine.com/Nirit-Yarom/2011/02/05/the- role-of-the-epidermal-growth-factor-receptor-in-the-mechanism-and-treatment-of-colorectal-cancer/ [Accessed: 15 Apr 2013]. Egfr-info.co.uk (2013). EGFR | Epidermal Growth Factor Receptor Testing, News and Resources. [online] Retrieved from: http://www.egfr-info.co.uk/ [Accessed: 15 Apr 2013]. Fujiwara, S. et al. (2012). Association of ErbB1–4 expression in invasive breast cancer with clinicopathological characteristics and prognosis. The Japanese Breast Cancer Society, Retrieved from: http://link.springer.com.dml.regis.edu/ [Accessed: 15th Apr 2013]. Topics.info.com (2010). Cancer Complications - topics.info.com. [online] Retrieved from: http://topics.info.com/Cancer- Complications_3416 [Accessed: 15 Apr 2013]. Voldborg, B. et al. (1997). Epidermal growth factor receptor (EGFR) and EGFR mutations, function and possible role in clinical trials. Annals of Oncology, 8 pp.1197-1206. [Accessed: 15th apr 2013]. Zhou, Q. et al. (2011). Relative abundance of EGFR mutations predicts benefit from gefitinib treatment for advanced non-small-cell lung cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 29 (24), pp.3316-3321.