Journal of Thoracic Oncology

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Running head: TOXICOLOGY AND PATHOLOGY
GENETIC ABERRATION IN LUNG CANCER
Name of the Student
Name of the University
Author Note

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Running head: TOXICOLOGY AND PATHOLOGY
Introduction
According to recent statistical reports, lung cancer has occupied a major part of the
population. There are two major categories of lung cancer named as non-small cell lung
cancer (NSCLC) and small cell lung cancer (Soria et al. 2018). The main compositions of
lung cancer are adenocarcinoma for 65% and 30% for squamous cell carcinoma. According
to various research studies, squamous cell carcinomas have been found to arise from a higher
mutation rate, which is mostly found in smokers. There is also a major type of lung cancer
known as EGFR mutation-positive cancer. One of the drugs known as osimertinib had shown
a survival without any cancer progression. The main molecular targets associated with lung
cancer include EGFR, ROS1, ALK and programmed cell death. Emerging (RET, MET and
NTRK) and elusive (MYC, KRAS, and TP53) are also the molecular targets for lung cancer
treatment. ENU mutagenesis (N-ethyl-N- nitrosourea) mutagenesis has been performed as in
various screening processes to identify the mechanism of resistance occurring in first and
second-line treatment with osimertinib (Lindeman et al. 2018). Most of the screening tests
proved that T790M resistance and C797S resistance were the most prominent resistances
observed in cases of lung cancer. This article will discuss the genetic aberrations associated
with lung cancer which includes the targets of drug use for the treatment of lung cancer. This
paper will also discuss the techniques to detect the targets for drug action during a condition
of lung cancer. Some of the most significant detecting the targets for drug action are NGS
(Next Generation Sequencing), Sanger sequencing and Real-time PCR (Polymerase Chain
Reaction).
Discussion
This section will review the existing reviewed and published pieces of literature
which focuses on the genetic alterations responsible for lung cancer and talks about the drug
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Running head: TOXICOLOGY AND PATHOLOGY
targets during the chemotherapy of lung cancer. According to Uchibori et al. (2018), EGFR
mutation is one of the most important underlying causes of lung cancer among the human
community. The survival rate of patients associated with EGFR positive mutation has
improved dramatically due to the introduction of EGFR-TKIs (EGFR tyrosine kinase
inhibitors). The first-line treatment used for lung cancer is EGFR-TKI showed a lower
survival rate than osimertinib. A significant reduction of lung cancer progression can occur
provided the person stops smoking. However, when lung cancer originates from a genetic
background, it becomes harder to control the progression. The authors successfully showed
that EGFR-TKI resistance mechanisms based on the first and second-line osimertinib by the
screening of ENU mutagenesis. According to the authors, T854A and C797S mutation has
been observed to afatinib resistance. According to Friedlaender et al. (2019) cancer of lungs
causes a high rate of mortality among the human population. Adenocarcinomas and
squamous cell carcinomas are the first disorders for which immunotherapy was discovered.
Treatment of targetable driver mutations is secondary. There are two major categories of lung
cancer named non-small cell lung cancer (NSCLC) and small cell lung cancer. The main
compositions of lung cancer are adenocarcinoma for 65% and 30% for squamous cell
carcinoma. According to various research studies, squamous cell carcinomas have been found
to arise from a higher mutation rate, which is mostly found in smokers. There is also a major
type of lung cancer known as EGFR mutation-positive cancer. A higher rate of mutation has
been observed for smokers since they are affected by squamous cell carcinomas. Two of the
most important problems in the identification of driver mutations and finding clinically
relevant mutations associated with lung cancer. According to the cancer genome Atlas,
frequent gene alterations have been used to identify the target of drugs required to neutralize
the mutation. Next-generation sequencing (NGS) has been observed to find the appropriate
landscape for the action of the drug against lung cancer. NGS has been used to identify the
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Running head: TOXICOLOGY AND PATHOLOGY
genetic rearrangements, copy number alterations, translocations and oncogenic fusion events
responsible for lung cancer. NGS is also cost-effective than other single-gene tests required to
identify the central; gene alterations responsible for the occurrence of non-squamous lung
cancer (NSCLC). NGS has also been observed as a highly specific and sensitive procedure to
test the potential impact of lung cancer and its effect after the action of therapeutic agents.
The primary genetic aberrations observed during the ERBB mutations, SqCC, and other
targets have been observed to be promising. TP53 mutations have been observed to be the
primary cause of lung cancer by NGS. Later, it has been stated that TP53 plays a major role
during the tumorigenesis process of epithelial lung cells. Cellular resistance to therapy has
been increasingly associated with genetic aberrations associated with lung cancer. In another
paper written by Gallant and Lovly (2018), it is stated that the identification of lung cancer as
a genetic disease cannot be rule out completely. The cancer taxonomies have been pushed
forward to categorize lung cancer according to the previously stated criteria. This study
successfully identified various mutations in genes responsible for the occurrence of lung
cancer. These mutated points in the gene is responsible for the secretion of abnormal proteins
that are targeted by various drugs used to treat lung cancer. The main genes responsible for
the occurrence of lung cancer are EGFR, ALK, ROS1 MET, NTRK and RET which are
directly targeted by drugs to reduce the progression of lung cancer. EGFR was identified as a
membrane-bound RTK (Receptor Tyrosine Kinase) which was used to search for epidermal
growth factor associated cognate receptor. EGFR was later recognized as the oncogene
inexorably linked with lung cancer. The emerging targets for lung cancer treatment include
(RET fusions, NTRK1/3 fusions, MET mutations, MET fusions, FGFR fusions, EGFR
fusions, HER2 mutations, AKT mutations, and RICTOR amp). Thus EGFR mutations have
been observed to be categorized under the group of emerging drug targets associated with the
treatment of lung cancer. The established targets for lung cancer include ALK fusions, ROS1

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fusions, BRAF mutations, PD-L1 expressions, and EGFR mutations. EGFR mutation has also
been grouped under the established drug targets proving that it is the central target for the
action of any drug that is responsible for the treatment of lung cancer. Finally, the elusive or
single molecular targets for lung cancer include four rare types of mutations including KRAS
mutations, NRAS mutations, MYC amp, and TP53 mutations. According to Lindeman et al.
(2018) lung cancer patients have been mostly treated with TTKI (Targeted Tyrosine Kinase
Inhibitors). The median survival rate of patients affected with lung cancer is 1 year which is
very low. ALK, EGFR, and ROS1 genes have been observed as the current targets for the
treatment of lung cancer. Some additional genes responsible for the occurrence of mutation
during lung cancer involves ROS1 testing which can be used for an appropriate lung cancer
treatment. Immunohistochemistry (IHC) has been observed to be highly sensitive in the
identification of various mutations responsible for the occurrence of lung cancer. The
oncogenic effects have been exerted by the coordination of selected hot spots (KRAS and
EGFR mutations). According to Gainor et al. (2016), PD-1 inhibitors have been observed as
the agents responsible for the management of non-small cell lung cancer (NSCLC).
PD-1/PD-L1 inhibitors activity is to be determined to understand the clinical relevance of the
molecular subgroups responsible for the occurrence of lung cancer. 3.6% of EGFR mutant
was observed as ALK-positive patients and 23.3% EGFR wild type have been observed as
ALK-negative patients. From the studies of these authors, it can be stated that EGFR
mutations harbor the ALK rearrangements responsible for the association of low ORRs with
PD-1/PD-L1 inhibitors. PD-L1 expression at low rates has been observed to be related to
CD8+ TILs inside the microenvironment of the tumor. This condition has been stated to be
the microenvironment that has underlying clinical conditions. According to Awad et al.
(2016), it can be stated that NSCLCs (non-small cell lung cancers) with mutations in the
MET exon 14 have flanking introns that respond to c-Met inhibitors. These 14 exons have
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been identified in MET within 28 or 933 NSCLCs (3.0%) which cannot be seen in other
types of cancers in this study. The 14 mutated regions of MET exon have been found to
represent a unique molecular subtype of NSCLC. Thus, it has been found that the exon 14
mutations are very much important as therapeutic targets in NSCLC. According to Rivzi et
al. (2015), there are various immune checkpoint inhibitors which can make the T cells of a
patient to kill tumors during the treatment of lung cancer. Pembrolizumab has been used to
treat non-small cell lung cancers which are an antibody targeting programmed cell death
(ATPCD)-1 or PD-1. One of the antigens (neoantigen-specific CD8+ T cell) responses for
tumor regression has been used in PD-1 therapy, which enhances the activity of T-cell
neoantigen. According to Thress et al. (2015) cfDNA (cell-free plasma DNA) isolated from
patients affected with lung cancer had tumors that developed resistance to EGFR (epidermal
growth factor) tyrosine kinase inhibitor. After the next-generation sequencing studies of
cfDNA from seven subjects were performed, an acquired EGFR C797S resistance was
observed. Another detection test responsible for the identification of T790M mutations at a
stage before the treatment process has begun. Thus T790M and C797S are the two molecular
targets for the drug. According to Mazieres et al. (2016), HER2 mutations are one of the
major causes of lung cancer in human beings. Chemotherapy with drugs is directly targeted
to GER2 in order to slow down the progression of cancer. These results have been collected
from the European EUHER2 cohort study which stated that HER2 mutations are the
oncogenic drivers associated with lung cancer and also have been found to be associated with
2% adenocarcinomas. Standard care has still not been devised for patients. NSCLC has been
observed to be sensitive to the chemotactic mechanism of HER2 targeted drugs. However,
due to less prevalence of the disease associated with HER2, it is estimated to take more years
to get the HER2 targeted drugs approved by the government. One of the most significant
drugs used for this treatment is Lapatinib which successfully slowed down the progression of
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Running head: TOXICOLOGY AND PATHOLOGY
lung cancer. Thus, this study had a primary weakness in the fact that it failed to identify the
other targets which were significantly more destructive than HER2 in the case of lung cancer.
However, in the paper produced by Morgillo et al. (2016) EGFR is the main target for the
treatment of lung cancer. Thus, the introduction of EGFR targeted drugs has begun with the
advent of EGFR tyrosine kinase inhibitors. Therefore, it can be stated that these are the
overall gene aberrations that are responsible for the occurrence of lung cancer. This section
has covered mostly all the targets to which the molecular drugs can act in order to prevent
lung cancer or to slow down the progression.
Conclusion
Although lung cancer begins in the lungs, it has an underlying genetic cause that
controls its growth and progression. Two types of lung cancers are prevalent in the human
community named as small cell lung cancer and non-small cell lung cancer. Lungs are
responsible for controlling the respiratory system of the human body. In Hong Kong, 3890
people have been calculated to have been dead due to lung cancer in 2017 as stated earlier.
According to the previous literature review section, people who smoke a lot, have been found
to be at a higher risk of lung cancer. A significant reduction of lung cancer progression can
occur provided the person stops smoking. However, when lung cancer originates from a
genetic background, it becomes harder to control the progression. EGFR has been identified
as the primary target for any drug which is used to treat lung cancer. There are three lines of
drug which can be administered to treat lung cancer depending on the cause ad stage.
However, various studies have also shown that the body can repair the ravage done by lung
cancer by itself also. Thus, it can be stated that a good future can be hoped to provide other
targets for lung cancer treatment that have been identified in the upcoming years.

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References
Awad, M.M., Oxnard, G.R., Jackman, D.M., Savukoski, D.O., Hall, D., Shivdasani, P., Heng,
J.C., Dahlberg, S.E., Janne, P.A., Verma, S. and Christensen, J., 2016. MET exon 14
mutations in non–small-cell lung cancer are associated with advanced age and stage-
dependent MET genomic amplification and c-Met overexpression. American Society of
Clinical Oncology (ASCO).
Friedlaender, A., Banna, G., Malapelle, U., Pisapia, P. and Addeo, A., 2019. Next generation
sequencing and genetic alterations in squamous cell lung carcinoma: where are we
today?. Frontiers in oncology, 9.
Gainor, J.F., Shaw, A.T., Sequist, L.V., Fu, X., Azzoli, C.G., Piotrowska, Z., Huynh, T.G.,
Zhao, L., Fulton, L., Schultz, K.R. and Howe, E., 2016. EGFR mutations and ALK
rearrangements are associated with low response rates to PD-1 pathway blockade in non–
small cell lung cancer: a retrospective analysis. Clinical cancer research, 22(18), pp.4585-
4593.
Gallant, J.N. and Lovly, C.M., 2018. Established, emerging and elusive molecular targets in
the treatment of lung cancer. The Journal of pathology, 244(5), pp.565-577.
Lindeman, N.I., Cagle, P.T., Aisner, D.L., Arcila, M.E., Beasley, M.B., Bernicker, E.H.,
Colasacco, C., Dacic, S., Hirsch, F.R., Kerr, K. and Kwiatkowski, D.J., 2018. Updated
molecular testing guideline for the selection of lung cancer patients for treatment with
targeted tyrosine kinase inhibitors: guideline from the College of American Pathologists, the
International Association for the Study of Lung Cancer, and the Association for Molecular
Pathology. Journal of Thoracic Oncology, 13(3), pp.323-358.
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Running head: TOXICOLOGY AND PATHOLOGY
Lindeman, N.I., Cagle, P.T., Aisner, D.L., Arcila, M.E., Beasley, M.B., Bernicker, E.H.,
Colasacco, C., Dacic, S., Hirsch, F.R., Kerr, K. and Kwiatkowski, D.J., 2018. Updated
molecular testing guideline for the selection of lung cancer patients for treatment with
targeted tyrosine kinase inhibitors: guideline from the College of American Pathologists, the
International Association for the Study of Lung Cancer, and the Association for Molecular
Pathology. Journal of Thoracic Oncology, 13(3), pp.323-358.
Mazieres, J., Barlesi, F., Filleron, T., Besse, B., Monnet, I., Beau-Faller, M., Peters, S.,
Dansin, E., Früh, M., Pless, M. and Rosell, R., 2015. Lung cancer patients with HER2
mutations treated with chemotherapy and HER2-targeted drugs: results from the European
EUHER2 cohort. Annals of Oncology, 27(2), pp.281-286.
Morgillo, F., Della Corte, C.M., Fasano, M. and Ciardiello, F., 2016. Mechanisms of
resistance to EGFR-targeted drugs: lung cancer. ESMO open, 1(3), p.e000060.
Rizvi, N.A., Hellmann, M.D., Snyder, A., Kvistborg, P., Makarov, V., Havel, J.J., Lee, W.,
Yuan, J., Wong, P., Ho, T.S. and Miller, M.L., 2015. Mutational landscape determines
sensitivity to PD-1 blockade in non–small cell lung cancer. Science, 348(6230), pp.124-128.
Soria, J.C., Ohe, Y., Vansteenkiste, J., Reungwetwattana, T., Chewaskulyong, B., Lee, K.H.,
Dechaphunkul, A., Imamura, F., Nogami, N., Kurata, T. and Okamoto, I., 2018. Osimertinib
in untreated EGFR-mutated advanced non–small-cell lung cancer. New England journal of
medicine, 378(2), pp.113-125.
Thress, K.S., Paweletz, C.P., Felip, E., Cho, B.C., Stetson, D., Dougherty, B., Lai, Z.,
Markovets, A., Vivancos, A., Kuang, Y. and Ercan, D., 2015. Acquired EGFR C797S
mutation mediates resistance to AZD9291 in non–small cell lung cancer harboring EGFR
T790M. Nature medicine, 21(6), p.560.

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Uchibori, K., Inase, N., Nishio, M., Fujita, N. and Katayama, R., 2018. Identification of
mutation accumulation as resistance mechanism emerging in first-line Osimertinib
treatment. Journal of Thoracic Oncology, 13(7), pp.915-925.
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