Introduction

 

Lung cancer is a multi-step process that involves DNA
adaptation which alters normal cells into malignant cells (Larsen, J., et al.,
2011). It is predominantly acknowledged that molecular mutation in
proto-oncogenes or tumor suppressor genes can result to cancer. Although
previous studies have focused on the diagnosis and treatment of lung cancer,
the 5-year survival rate for patients requires improvement. Lung cancer is one
of the dominating causes of cancer-associated mortality. Due to these poor
clinical outcomes, there has been substantial research into the mechanisms of
pathogenesis of this disease. Advances in molecular biology and pathogenesis of
lung cancer provide insights into potential therapeutic targets. Investigators
have identified multiple processors that are responsible to the contribution of
tumour progression and responsible for cell growth (Pendharkar, D., et al.,
2013). This review highlights some of the significant molecular configuration
of lung cancer, diagnostic, therapeutic target, and its clinical
implications. 

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Types of
lung Cancer

 

Lung
cancer is classified into two main types: non-small cell lung cancer (NSCL) and
small cell lung cancer (SCLC) accounting to 85 percent and 15 percent of all
lung cancers, respectively. NSCLC is clustered into three subtypes:
adenocarcinoma, squamous cell carcinoma, and large cell lung carcinoma. It is
the second commonest cancer in both gender. Mortality rate of lung cancer is
getting higher, combined with high recurrence rate, it is usually detected at
the late stage. Additionally, lung cancer does not present signs and symptoms
during the initial stage.

SCLC
develops rapidly and metastasize to other tissues, usually to the liver, brain,
bones and adrenal glands. Survival rate is usually one year after diagnosis of
cancer (American., anon; Larsen, J., et al., 2011; Langevin, S.,).

 

 

Molecular
etiology of lung cancer

 

Development of lung cancer is related with multiple
chromosomal and epigenetic adaptations affecting apoptosis and cell
proliferation (tumor suppressor genes and oncogenes). Tumor suppressor genes
that are associated in lung cancer carcinogenesis are also linked with
prognosis (Davis, M., et al., 2014). Tumor suppressor genes are commonly
altered in the early stage of lung cancer (Yunxi, J., et al., 2017).

RAS play an active role
mainly in controlling cell division, (molecular., anon) and also the commonly
altered proteins. It is the fundamental mediators for signal transduction and cell multiplication, comprising K-RAS, H-RAS, and N-RAS. Activation of
downstream signaling pathways (PI3K and MAPK- mitogen-activated protein kinase)
would result in mutation. This would cause
KRAS altered tumors independent of EGFR signaling, hence, making it resistant
to EGFR TKIs (Larsen, J., et al., 2011). In order for the RAS to be activated, it has to bind with guanosine triphophate (GTP). On the other hand,
it is deactivated by GTPase -activating protein (GAP) by breaking down
guanosine triphosphate to guanosine diphosphate (GDP). Alterations at or around
the GTP-binding domain of RAS gene inhibits the deactivation of GTP, thus
causing in uninterrupted RAS activity (Singh, C., et al., 2014).  Mutation
occur due to exchange in position of amino acid 12,13 or 61 (Zappa, C., et al
2016).

HER-2 protein is a growth factor receptor belonging to the tyrosine kinases
group comprising of EGFR/ERBB1, HER2/ERBB2/NEU, HER3/ERBB3, and
HER4/ERBB4.  Insertion in exon 20 leads
to kinase activity and heightened signaling by means of downstream pathways. This mechanism will promote
tumorigenicity and pathogenesis. HER2 alterations
are discovered in approximately 2–4% of NSCLC cases, develop generally in adenocarcinomas
of never smokers females (Roh, M., et al., 2014).

PTEN genes involves in the
regulation of cell division by controlling cell multiplication in controlled
manner, hence, mutation would result to uncontrolled cell multiplication. Research
established that this enzyme conserves the cell’s genetic information, and
regulates migration, adhesion and angiogenesis (molecular., anon).

EGFR gene feeds directions for producing a small chemical, the epidermal growth factor receptor, which are generated by a cell and
bind to other protein (ligand) on the same cell or outside the cell – like
fitting of a key into locks. The attachment of the ligand to the epidermal
growth receptor will create a chemical reaction inside the cell. This will
trigger activation of signal pathways promoting controlled cell growth and
proliferation. In cancer, the mutated gene “believes” the growth factor is bind
though it is actually not attached. As a result, the tumor cell proliferates
uncontrollably. F (Kobayashi, K., et al., 2013). Alteration usually happen in
exon 18-21, but 90% of deletion and point alteration take place in exon 19 and
L858R, respectively (Zappa, C., et al 2016).

P53 regulates cell cycle, initiates apoptosis and preserve genome integrity,
also works as a master growth regulatory switch (Singh, C., et al., 2014). Alterations mainly suggest G to T substitution caused by bulky DNA adducts
(Massion, P., et al., 2003). P53 gene will affect tumor-suppression functioning resulting to uncontrolled cellular
proliferation. P53 was the
frequently mutated protein in lung cancer in both SCLCs and NSCLCs, approximately 100 % and 90 %, respectively. P53 genes has the capacity to
transform by binding with normal P53 and then inactivate itself (Singh, C., et
al., 2014; Larsen, J., et al., 2011).

Anaplastic Lymphoma Kinase (ALK) is a growth factor receptor that can be seen in cancer cells.
Generally, it can be found in adult’s brain tissue and researched has
established that it is vital receptor in fetal development. In the course of
cell mutation, intron 10 will merge with intron 13 and “turn it on” resulting
in cancer multiplication (Roh, M. 2014; Eldridge, L. 2017).

BRAF
is a serine/ threonine kinase molecular pathway that is responsible for the
regulation of cell multiplication. It can be found on the upper part of the MEK
and ERK signalling cascade. BRAF mutation will stimulate MEK and ERK
resulting to cancer cell activation. (Guanghui, C., et al.,).