Transcript Epidermal Growth Factor Receptors (ErbB

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
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).
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from
http://www.surgical
notes.co.uk/?q=nod
e/369
Introduction
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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)
Introduction
• Mutations in the Tyrosine kinase domain of the protein are also observed,
resulting in more intracellular downstream signaling (http://Egfrinfo.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-ofthe-epidermal-growth-factorreceptor-in-the-mechanism-andtreatment-of-colorectal-cancer/
Brief History
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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
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https://www.tracy.k12.ca.us/sites
/jrio/Pages/WorldHistory.aspx
Symptoms and Complications
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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
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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 cetuximab (Erbitux®) or panitumumab (Vectibix®)
Inhibitors also stop the continous signal of growth, possibly leading to cell death
and cessation of tumor metastasis (http://cepmed.dnadirect.com. 2013)
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
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-targetedtherapy.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/therole-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/CancerComplications_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.