Key Mutations and Treatments of Lung Cancer

Lung cancer has become the most prevalent and threatening cancer worldwide. Parallel to most malignancies, lung cancer is composed of sub-populations of cells with distinct molecular features, resulting in intra-tumoral heterogeneity (Herbst, et.al, 2018). There are two types of lung cancer; small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) (Molina, et.al, 2008). NSCLC accounts for around 85% of all cancer incidents, whereas SCLC only accounts for 15% (Herbst, et.al, 2008). NSCLC can be further divided into three main sub-types; squamous cell carcinoma, which contributes to 25-30% of all lung cancers, adenocarcinoma, which contributes to 40% and large cell carcinoma, contributing 10-15% (Gilad, et.al, 2012). As shown in figure 1, lung cancer develop throughout the lung at different areas. The development of the cancer can be defined by stages, all describing the cancers size, position and its metastasis status. When the tumour is localised within the lung and is 75% of SCLCs and about 50% of NSCLS (Fong, et.al, 2003). Again, mutations within p53 are related to smoking. Three key mutations occur at codons 157, 248 and 273. Within these hotspots, G:C to T: A mutations occur (Toyooka, et.al, 2003).

Evading Apoptosis

Apoptosis is the process of programmed cell death that organisms have acquired to eradicate unhealthy or toxic cells within the body, in response to cellular stress. The deregulation of apoptosis is a major component of tumour growth and progression. Bcl2 family proteins regulate apoptosis along the intrinsic mitochondrial apoptosis pathway, that is activated in the response to several stress stimuli, including growth-factor deprivation, cytokine withdrawal, calcium ion fulgurations or DNA damage (Frenzel, et.al, 2009). The Bcl-2 family is comprised of anti-apoptotic proteins and pro-apoptotic proteins. When the balance of these two sub-groups of proteins is disturbed, apoptosis is deregulated, allowing the accumulation of toxic cells (Wong, 2011). The unbalance can be caused, by either an overexpression of anti-apoptotic Bcl-2 proteins, or an under-expression of pro-apoptotic proteins. Bcl2 proteins are anti-apoptotic proteins located within the outer mitochondrial-membrane. Blc-2 protein forma a heterodimer with pro-apoptotic proteins, like BAX, leading to their inactivation. BAX is a downstream transcription of p53, and therefore, if there are disruptions within p53 expressions BAX can also be affected (Panov, 2005). In lung cancer, BCL-2 overexpression was found in 75-95% of SCLC tumours, 25-30% of the squamous cell carcinomas and in 10% of adenocarcinomas (Kaiser, et.al, 1996) Moreover, high Bcl-2 expression and low BAX expression occurs in most SCLC tumours which also have p53 deficient (Larsen, Minna, 2011).

Limitless Replicative Potential: Telomerase

Telomeres are nucleoprotein structures located at the end of chromosomes, consisting of repetitive sequences of TTAGGG and are associated with telomere-binding protein complexes (Albanell, et.al, 1997). The telomeres of somatic cells shorten with every mitotic division, as DNA polymerase is unable to fully replicate the 3’ end of DNA. Telomeres function to cap the ends of chromosomes to prevent the chromosomes form degradation, end-to-end fusion and irregular recombination and if faulty can increase the formation of tumours. Telomerase is an RNA -dependant DNA polymerase that contains template RNA and catalytic reverse transcriptase. The enzyme is responsible for adding telomeric DNA repeats after each cell division, maintaining telomere length and function (Jeon, et.al, 2012). Cells in which telomerase is active become immortal and can divide indefinitely (Dobja-Kubica, et.al, 2016). The consequence of this is that if the telomere is activated after the interaction of an oncogene or other mechanisms of carcinogenesis then the newly formed tumour cell will become immortal. A high telomerase activity was detected in almost 100%of SCLC and 80% of NSCLC (Panov, 2005). With NSCLC, high activity of the enzyme was associated with increased proliferation rates and advanced pathologic stage (Herbst, et.al, 2005).

Sustained Angiogenesis

The growth, progression and metastasis of tumours is critically dependant on a functional vascular supply. Angiogenesis is the formation a new blood vessel, which provided tumours with the blood supply they need (Herbst, et.al, 2005). Under moral conditions, angiogenic is tightly regulated by a balance of pro-angiogenic and anti-angiogenic factors. However, in cancer, angiogenesis increases due to an increase in activation of pro-angiogenic factors and involves both the alteration of existing structures and mobilization of progenitor cells (Alevizakos, et.al, 2013). Vascular endothelial growth factor (VEGF) is the main mediator of angiogenic in lung cancer. VEGF plays a significant role in several processes that result in angiogenesis. Firstly, VEGF losses the connections between endothelial cells and production of nitric oxide. This increases permeability and vasodilation of blood vessels (Dong, Ha, 2010). Furthermore, BEGF induces the expression o f proteases which dissolve the extracellular matrix around the vessels. This results in the release of other pro-angiogenic molecules and creates space for new vessels to form (Alevizakos, et.al, 2013). In addition, VEGF promotes the recruitment of endothelial progenitor cells and other bone marrow-derived cells, providing the newly forming blood vessels with a source of dividing cells and more pro-angiogenic factors (Melero-Martin, Juan, 2011). Both NSCLC and SCLC express VEGF, with adenocarcinomas having the highest level of VEGF expression (Korpanty, et.al, 2010). It has been shown that males with the 634C allele of the VEGF gene are at higher risk of developing adenocarcinomas of the lungs (Jain, et.al, 2009). VEGF can be used as a prognostic indicator in lung cancer. It has been recorded, that VEGF overexpression results in a decreased chance of survival (Zhan, et.al, 2009). Furthermore, high expressions of VEGF189 ratio (an isoform of VEGF) has been associated with a significantly shorter survival rate (Jain, et.al, 2009).

Treatments

How lung cancer is treated depends on a number of factors including; the patients health, the stage of cancer, they type of cancer and the location within the lung and the rest of body. As mentioned above, the best treatment for early stage I cancer, whether it is NSCLC or SCLC is surgical removal of the tumour. Because at stage one, the tumour is small and contained within a specific area, it can be easily removed. Furthermore, to prevent a reoccurrence of the cancer, patient can then undergo adjuvant therapy. This included radiation, chemotherapy and targeted therapy (Zappa, Mousa, 2016). However, 40% of newly diagnosed lung cancer patients are stage IV, and therefore surgical removal is not an option. When surgery is not an option, patients can receive chemotherapy or radiotherapy to try and treat lung cancer (Zappa, Mousa, 2016). Due to the aggressiveness of SCLC, treatments tend to be limited to a combination of chemotherapy treatments and radiotherapy (Cooper, Spiro, 2006)

Because of advances in genetic screening and biomarker testing, targeted therapeutic treatments are being developed and tested worldwide. Biomarkers can be used for personalised treatment and prognostics. Personalised medicine by targeting appropriate molecular targets in tumours has helped improve survival in lung cancer patients. This is a prominent technique used in patients with NCLC. One key biomarker is EGRF mutations. Patients exhibiting EGFR mutations tend to be prescribed Tyrosine Kinase (TK) inhibitors. One specific TK inhibitor which is prescribed to patients which show high levels of EGRF mutation is Gefitinib. Anti-EGRF antibodies have also been used to target and treat EGRF related cancers (Pao, et.al, 2004). However, these treatments aren’t perfect with only 10% of patients responding positively to these treatments alone. Therefore, another biomarker used for targeted therapeutics is KRAS. As KRAS is downstream to EGFR, it is used as a biomarker for patients resistant of EGRF drugs (Riely, Ladanyi, 2008).

Concluding Remarks

Even though lung cancer is a prominent disease, diagnosing and treating it is difficult due to its complexities. However, there is light at the end of the tunnel. Now countries are associating lung cancer with smoking, regulations are being put in place, reducing incident numbers. Furthermore, developments within the last decades in diagnostics and treatment are showing promising results. New molecular targets are continuously being found increasing the possibility of new therapeutics and reducing drug resistance within patients.