1. 1
Bioscience & Chemistry Programme
Professional & Scientific Practice 3
Evaluating the pathogenesis of Lung Adenocarcinoma in relation to
NICE treatment guidelines and futuristic treatment developments
By Adam Boulger
B7040016
Submitted Date: 21/02/2020
3. 3
Evaluating the pathogenesis of Lung Adenocarcinoma in relation to
NICE treatment guidelines and futuristic treatment developments.
Abstract
Non-small cell lung cancer (NSCLC) is the deadliest form of cancer, accentuating the
clinical demand for more effective treatments in addition to the introduction of early
detection programs. Genomic advancements are driving the understanding around
the underlying pathogenesis by identifying recurrent MAPK/PI3K and cell cycle
pathway dysregulation. Current targeted treatment approach against epidermal
growth factor receptor (EGFR) and programmed death-ligand 1 (PD-L1) enable
median survival of 216 days against non-targeted 203 days. An underappreciation
towards copy number alterations could be a contributing factor and in recent years,
advancements are focusing upon human epidermal growth factor receptor-2 (Her-2),
Kirsten rat sarcoma (K-Ras) and cyclin-dependent kinases 4/6 (CDK-4/6) inhibitors
4. 4
present the potential to increase disease survival rates. Although, rapid and
considerable progress are required due to the poor survival and a lack of specific
patient cohorts, hindering developments through a bottleneck in clinical trials.
1. Introduction to Lung Adenocarcinoma
Lung cancer is the second most prevalent type of cancer for both males and females across
the UK (UK Office for National Statistics, 2018). UK government figures from 2017 outlined
38,888 cancer registrations, consisting of 12.7% of the total cancer burden (UK Office for
National Statistics, 2019) forming the deadliest form of cancer and attributed as the fifth
leading causation of death with around 30570 deaths during 2017 (UK Office for National
Statistics, 2017). This figure, which is greater than breast, colon and pancreatic cancers
combined (Zappa, & Mousa, 2016), exemplifies the importance of reviewing and researching
lung cancer to improve the approach of diagnosis and treatment of lung cancers. Lung cancer
is divided into 13% patients with small-cell and 87% NSCLC (National Health Service, 2020).
Although, this is potentially simplified as a major flaw was identified by NHS statistics stating
only 72% of lung cancer patients are confirmed by phenotypic or molecular genotyping
(NICE, 2017). It could be suggested that this is in relation to around 70% of individuals being
diagnosed at an advanced disease state, commonly stated as terminal (Molina, Yang,
Cassivi, Schild, & Adjei, 2008). However, research concurs that the major histological form
of NSCLC is adenocarcinoma and is accepted as the leading cause of cancer deaths
worldwide (Collison et al, 2014), with Reis et al identifying the relative frequency being 90.9%
of cases (Reis et al, 2020). Although, comparative analysis with a 2019 publication
commissioned and implemented by NHS identified adenocarcinoma at 60% (Crosbie et al,
2019). This agreement outlined the most prevalent sub-type, whilst highlighting clear issues
with data standards and a lack of consistency. Until recently, it was thought major sub-types
could be characterised by their antithetical anatomical tumour locations, with
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adenocarcinoma being peripheral (Kadara, Scheet, Ignacio, & Spira, 2016), but this is no
longer assumed following Moon et al’s publication highlighting 13.3% of cases being central
bound (Moon, Lee, Sung, & Park, 2016). This could suggest reasoning behind the
discrepancy identified in the data, therefore, these statistics may not be comparable or
accurate. A current focus is upon early diagnosis, with a Manchester research screening pilot
across 1384 high risk individuals produced diagnostic results showing 80.4% patients
diagnosed at stages I/II compared to the standard of 31% and advanced stages III/IV at
19.6% compared to standard of 69%, with the biggest decrease being for stage IV from 48%
to 11% (Crosbie et al, 2019). Furthermore, another screening trial reduced mortality by 26%
in men and up to 61% in females (Yousaf-Khan et al, 2017). This directly correlates to findings
by McPhail et al, stating that an earlier diagnosis directly correlates to an increased rate of
survival (McPhail, Johnson, Greenberg, Peake, & Rous, 2015). This review will evaluate the
current understanding of pathogenesis in relation to current and futuristic treatment
approaches.
2. Genetic analysis to identify underlying pathological mechanisms
Across adenocarcinoma, difficulties identifying the cell of origin have historically hampered
the understanding of initiation and progression pathogenesis studies (Devarakonda,
Morgensztern, & Govindan, 2015), with alveolar type II cells now accepted as the origin of
adenocarcinoma (Kim et al, 2005., Lin et al, 2012). Critically, the issues with cell of origin still
exist with central adenocarcinoma. To elucidate the pathogenesis of adenocarcinoma, The
Cancer Genome Atlas Research Network (TCGARN) published a large-scale genome project
(Collison et al, 2014) to identify prevalent recurrent genetic alterations to be identified in those
with adenocarcinoma. This data can be mapped in accordance to affected pathways to
suggest the basis of underlying pathological mechanisms. Critically, a major issue with
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TCGARN’s publication was the focus upon point mutations rather than copy number
alterations, although the copy number alteration data was provided.
Figure 1: 2-D Bar Chart presenting percentage (%) Lung adenocarcinoma patients with somatic point mutation
(missense, nonsense, in-frame deletion, frameshift) against correlating gene. Selected all >10%. Created using
The Cancer Genome Atlas Research Network’s publication of data (Collison etal,2014).Loss of function (LOF)
mutation to TP53, KEAP1, STK11 and NF1. Gain of function (GOF) mutation to KRAS, EGFR, BRAF.
0 5 10 15 20 25 30 35 40 45 50
BRAF
NF1
EGFR
SKT11
KEAP1
KRAS
TP53
% Patients
Geneaffected
RecurrentLung adenocarcinomapatient point mutations
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Figure 2: 2-D Bar Chart presenting % patients presenting with low-medium copy number amplification to a
gene. Selected all >10%. Constructed using raw genetic data from supplementary data from The Cancer
Genome Atlas Research Network 2014 publication (Collison etal,2014).
0 10 20 30 40 50 60 70
RBM10
HRAS
AKT1
CCNE1
U2AF1
MDM2
CDK4
NRAS
PI3KCA
ARID1A
KRAS
TERC
CCND1
NKX2-1
MET
NF1
BRAF
ERBB2
EGFR
TERT
MYC
RIT1
% Patients
GeneAffected Recurrentlow-mediumcopy number amplifications inLung
adenocarcinomapatients
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0 2 4 6 8 10 12 14 16 18 20
TERT
RIT1
NKX2-1
MYC
MDM2
EGFR
CDK4
KRAS
% Patients
GeneAffected Recurrenthighcopy number amplificationinlung
adenocarcinomapatients
Figure 3: 2-D Bar Chart presenting % patients presenting with a specific high copy number amplification to a
gene. Selected all >5%. Constructed using raw genetic data from supplementary data from The Cancer
Genome Atlas Research Network 2014 publication (Collison etal,2014).
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The underlying disease mechanisms are yet to be understood (Chen et al, 2018)
with Zhang et al highlighting this difficulty due to the complex heterogeneity (Zhang,
Chang, & Yang, 2019). However, research has a collective acceptance that the
MAPK and PI3K pathways are essential drivers (Wu et al 2019., Pradhan et al
2019). This in relation to 75% of patients presenting with direct oncogenic alterations
driving Ras activity (Inamura, 2017) and 62% of patients presenting direct mutations
to KRAS and EGFR (Kadara et al, 2016., Yap et al, 2014) with an average of 8.9
mutations per million bases (Collison et al, 2014).
0 10 20 30 40 50 60
CDKN2A
SETD2
RB1
KEAP1
SMARCA44
STK11
MGA
TP53
% patients
GeneAffected
Recurrent gene deletions in lung adenocarcinoma
patients
Figure 4 : 2-D Bar Chart presenting % patients presenting with genetic absence of a gene. Heterozygous loss is
coded as blue and homozygous loss (2L) is orange. Heterozygous loss selected top 8 most common, majority of
Homozygous loss only present as affecting CDKN2A, second most common was gene MGA with 3.04% patients
affected. Constructed using raw genetic data from supplementary data from The Cancer Genome Atlas
Research Network 2014 publication (Collison etal,2014).
CDKN2A
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2.1 MAPK & PI3K/mTOR pathway dysregulation drives pathogenesis
Figure 5: Created using data outlined in Figures 1, 2, 3 and 4 to review the major pathway modifications to
signalling pathways involved in propagation and pathogenesis by identifying recurrent pathogenic drivers to
suggest potential treatment approaches to lung adenocarcinoma. Diagram created to review and collate the
plethora of recent advancements and publications in the field of adenocarcinoma utilising information from
(Collison etal,2014.,Singh et al,2013., Reis et al,2020., Cheung, & Nguyen, 2015., Cheng, Alexander, &
MacLennan, 2012., Greulich,2010., Berger, Imielinski,& Duke, 2014., Kadara et al,2016., Korneeva, Song,
Gram, Edens, & Rhoads, 2015.,Siddiqui,& Sonenberg, 2015., Jahangiri,& Weiss,2013.,Gul,Leyland-Jones,
Dey, & De, 2018., Hemmings, & Restuccia,2012.,Ozenne, Eymin, Brambilla,& Gazzeri, 2010).Key: green
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arrows represent activation, red arrows represent inhibition, orange boxes highlight oncogenes and grey boxes
highlight tumour suppressor genes. Abbreviations: GOF, gain of function, LOF, loss of function, LMA, low
medium amplification, HA, high amplification, -1hl heterozygous loss, -2hl, homozygous loss.
Chen et al highlighted that although the underlying disease mechanisms have yet to
be elucidated, their research analysing KEGG pathway enrichment highlights the
importance of the cell cycle and cancer pathways (Chen et al, 2018). Recent
publications by Pradhan et al and Wu et al highlight the importance of MAPK and PI3K
cancer pathways as essential for pathogenesis by driving the cell cycle (Wu et al
2019., Pradhan et al 2019).
Across the genomic landscape of adenocarcinoma, Figure 5 presents the recurrent
receptor alterations to MET, ERBB1and ERBB2 which directly induce MAPK and PI3K
signalling (Collison et al, 2014) leading to proliferation, evasion of apoptosis and
angiogenesis (Sun et al, 2015., Liu, Jin, Wang, & Wang, 2017). The most prevalent is
ERBB1, presenting two recurrent gain of function (GOF) aberrations which consist for
90% total mutation burden with exon 21 p.L858R (Wan, Wright, & Coveney, 2012) and
micro-deletion p.del19 which directly increase pro-oncogenic downstream signalling
(Imielinks et al, 2012., Jakobsen, Santoni-Rugiu, Grauslund, Melchior, & Sørensen,
2018) in addition to 47% of patients presenting copy number amplifications (Collison
et al, 2014). This is supported by Kadara et al and Reungwetwattana et al indicating
the involvement of ERBB1 and Ras family alterations as the most prominent driver
mutations (Kadara et al, 2016., Reungwetwattana, Weroha, & Molina, 2012), with Lee
et Bae highlighting K-ras as an important event in the early initiation of
adenocarcinoma (Lee, & Bae, 2016). As illustrated in Figure 5, the intercalation
between MAPK and PI3K can be driven by K-ras, presenting 33% and 33.5% of
patients with GOF and amplifications respectively (Collison et al, 2014). Jordan et al
identified the most prevalent somatic alteration as p.G12C across both primary and
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metastatic patients (Jordan et al, 2017), which links to alternative research highlighting
this mutation leads to greater oncogenic activity by higher extracellular signal-related
kinase 1/2 (ERK) downstream activatory phosphorylation in comparison to p.G12D
(Yang, Liang, Schmid, & Peng, 2019., Li et al, 2018) which drives downstream MAPK
activity. This suggests that analysing gene heterogeneity could lead to an improved
pharmacogenomic approach.
The Kegg publication identified the key effectors of the MAPK pathway as c-Jun, c-
Fos, Ets1, MSK1 and c-MYC (Kyoto University Bioinformatics Centre, 2019). ERK’s
phosphorylate and activate ETS-Like-1 protein (Elk-1) and Ets-1 transcription factors
which rapidly upregulate the Jun and Fos proto-oncogene families, with Kegg
highlighting the up-regulation of c-Fos and c-Jun proteins as key which form activator
protein-1 (AP-1) heterodimers (Kyoto University Bioinformatics Centre, 2019.,
Atsaves, Leventaki, Rassidakis, & Claret, 2019) . A landmark paper identified the c-
Fos:c-Jun heterodimer exhibits higher transactivation in comparison to alternatives
such as JunB or JunD (Chiu, Angel, & Karin, 1989). This activity is activated upon the
transcriptional activation domain of c-Jun at sites p.Ser63 and p.Ser73 being
phosphorylated by c-Jun N-terminal terminal kinases (JNK) (Zhao, Wang, & Tony,
2015), with Tanos et al identifying c-Fos is activated by P38 MAPK phosphorylation
(Tanos et al, 2005). A key finding, highlighted by Alonso et al, is c-Jun promoter and
AP-1 exhibiting a high affinity, therefore, it could be suggested that a positive feedback
loop exists with this perpetual and self-activatory action exacerbating pathogenesis by
increasing AP-1 levels (Alonso et al, 2018), with Figure 5 outlining AP-1 upregulating
cyclins, CDK’s and activating E2F transcription factors.
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The identification of an underlying driver could lead to rapid progression in the
treatment of NSCLC adenocarcinoma. Elangovan et al’s breakthrough research
discovered Fos family, Fos-like antigen-1 (FOSL-1) as a major effector of RAS-MAPK
signalling, presenting FOSL-1 expression as a critical determinant of the
tumourigenesis of NSCLC adenocarcinoma, highlighting that emerging data is
indicating that FOSL-1 expression and poor survival are directly correlated (Elangovan
et al, 2018). These findings were developed upon Vallejo et al’s publication, with data
identifying FOSL-1 up regulation in mutant K-ras mutant (p.G12D) cell lines by multiple
downstream kinases via an autonomous mechanism (Vallejo et al, 2017). With the key
transcriptional regulators being ATF-2, MYC and AP-1 (Lopez-Bergami, Lau, & Ronai,
2010), with a finding identifying a key role of MSK1, by phosphorylating histone H3S10
to induce the transcriptional elongation of FOSL-1, C-Jun and C-Fos (Zippo et al,
2009). This links directly back to Kegg publication highlighting c-Jun, c-Fos, Ets1,
MSK1 and c-MYC as the major factors (Kyoto University Bioinformatics Centre, 2019)
whilst portraying the symbiotic self-activatory activities of the constituents.
Furthermore, as indicated by Figure 5, Warne et al identified the MAPK/PI3K
intercalation by Ras activation of PI3K (Rodriguez-Viciana, Warne, Vanhaesebroeck,
Waterfield, & Downward, 1996), with Castellano et Downard’s publication presenting
the PI3K pathway as essential in RAS mutant in-vivo tumourigenesis studies with
PI3KCA’s p.Lys227 being essential in this intercalation activation (Castellano, &
Downward, 2011), with 24% of patients presenting amplifications (Collison et al,
2014). However, Nussinov et al recently highlighted the difficulty in identifying the
mechanism by which this occurs (Nussinov, Tsai, & Jang, 2019). An investigation into
whether Ras heterogeneity (such as K-ras p.G12C>p.G12D discussed above) can
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induce variable levels of PI3K activity could lead to breakthrough findings. This
essential Ras:PI3KCA interaction was disrupted by Castellano et al in Ras driven
adenocarcinoma and this led to regression by an autonomous mechanism (Castellano
et al, 2013). This was also found by Murillo et al in mutant ERBB1 cells, where
disrupting Ras:PI3KCA inhibited tumourigenesis and also induced regression in
established adenocarcinoma (Murillo et al, 2018). Furthermore, Veen et al recently
published findings with mutant BRAF (p.V600E) cells unable to initiate
adenocarcinoma tumourigenesis unless co-expressed with PI3KCA pathway mutant
(p.H1047R), compared to mutant K-ras (p.G12D) being able to solely induce
tumourigenesis, which is directly associated to RAS:PI3K cross-interaction (Veen et
al, 2019). Upon this, it could be suggested that this interaction is a major underlying
factor in the pathogenesis, even with a critical flaw in Veen et al’s methodology using
PI3KCA mutant not present in TCGARN’s data (Collison et al, 2014). Wang et al
highlighted across their study into PI3KCA mutant patients that 86% had coexisting
mutations in ERBB1 or K-Ras (Wang et al, 2014). However, Tang et al presented
findings which suggested all patients present with co-existing mutations (Tang, Zhang,
& Lu, 2018). Although, it could be suggested that a key flaw across papers is the
incomparable selection of individuals, therefore, this could lead to inaccurate
comparative analysis between papers. Meng et al presents an example of this by
focusing only upon Chinese patients (Meng et al, 2019).
Furthermore, TCGARN highlight unknown mechanisms of MAPK/PI3K activation exist
(Collison et al, 2014), which could link to the under appreciation of copy number
alterations mostly under appreciating the alterations to HRAS, NRAS and RIT1 genes.
TCGARN data presents 1% of patients present with somatic mutations to these genes
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(Collison et al, 2014). However, including analysis of copy number alterations
identifies high levels of amplifications, with 16%, 23% and 74% patients presenting
amplifications respectively. Critically, Figure 5 shows patients can present with loss of
function (11%) or amplifications (37%) to NF1, which Yap et al outline is a tumour
suppressor by suppressing Ras activity (Yap et al, 2014). This would indicate NF1
reduces MAPK/PI3K activity, although, questioning the understanding of the role of
NF1 could lead to novel findings around the functionality as recurrent amplifications to
a tumour suppressor with current understanding would not assume to induce
adenocarcinoma. This is yet to be analysed in relation to adenocarcinoma, but breast
cancer patients present 17% NF1 amplification, with Philpott et al suggesting it is
important for the pathogenesis (Philpott, Tovell, Frayling, Cooper, & Upadhyaya,
2017). It could be suggested that NF1 presents oncogenic properties with certain
genomic profiles, potentially an investigation into whether NF1 repressing RAS: MAPK
leads to an increase of RAS:PI3K interaction.
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2.2 Cell Cycle propelled by MAPK/PI3Keffectors
Figure 6: Constructed upon Figures 1, 2, 3, 4 and 5 to review the major pathway modifications to the cell cycle
pathway. Key: green arrows represent activation, red arrows represent inhibition, orange boxes highlight
oncogenes, pink highlight transcription factors and grey boxes highlight tumour suppressor genes. References;
(Collison etal,2014., Singh et al,2013.,Reis et al,2020., Cheung, & Nguyen, 2015., Cheng et al,2012.,
Greulich,2010., Berger et al,2014., Kadara et al,2016).
The role of MAPK/PI3K outlined in Figure 5, in addition to Figure 6, highlights the recurrent
cell cycle alterations, which is a clear presentation of the correlation and symbiotic nature of
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pathway alterations leading to R-point passage for S-phase which is understood as the ‘point
of no return’ for cellular proliferation (Matson, & Cook, 2017). As presented by Figure 6, PI3K
effector ATK1 inhibits P53 with ATK1 and MDM2 both present with recurrent amplifications,
highlighting the essential inhibition of P53 (Collison et al, 2014). This is also evident by 61%
patients presenting a form of CDK2NA loss and this prevents the inhibition of MDM2.
(Collison et al, 2014). Furthermore, this is also evident by 46% and 55% of patients
presenting with TP53 LOF or heterozygous deletion respectively. This finding is key as in
cases of heterozygosity, mutant P53 exhibits the ability to antagonise wild-type P53 in a
dominant-negative manner by inhibiting tetramer formation (Rivlin, Brosh, Oren, & Rotter,
2011). Alexandrova et al suggests this could underestimate true P53 loss of function
(Alexandrova, Mirza, & Xu, 2017). Although, Lee et Bae stated that it is currently unclear
whether TP53 inactivation is the progression or initiation of pathogenesis (Lee, & Bae, 2016).
Investigations by Junttila et al & Feldser et al induced adenocarcinoma by mutating Ras/TP53
and reversing this led to regression (Junttila et al, 2010., Feldser et al, 2010). Furthermore,
Junttila et al identified Ras mutants are a potent trigger of P53 and the oncogenic driving
action of Ras mutants is selective for the acquisition of mutant TP53 genes (Junttila et al,
2010), whilst Feldser et al highlighted MAPK signalling as a critical determinant of
adenocarcinoma (Feldser et al, 2010). This is the basis which enables the extreme
accumulation of mutations.
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3.0 Current Treatment Approach to NSCLC Adenocarcinoma
Figure 7: Adapted from NICE guidelines illustrating current clinical algorithm (National Institutefor Health and
Care Excellence, 2019).Altered to remove ALK analysis following TCGARN data (34) which presented <1%
adenocarcinoma patients with ALK mutant. This is a flaw in the current practice due to grouping into
‘squamous’ and ‘non-squamous’ forms.
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Khakwani analysed UK NSCLC survival trends identifying a slight survival
improvement due to increased surgery rate, even with an increasing proportion of
NSCLC adenocarcinoma (Khakwani et al, 2013). The current treatment algorithm is
fundamentally flawed with the NHS 2019 Lung Cancer audit stating 67.3% and 37%
of patients achieved three-month survival and one-year survival respectively with only
18.4% of patients undergoing surgical cancer removal and 40% of stage IIIB patients
not receiving treatment (Royal College of Physicians, 2018). Furthermore, a 2020
audit on molecular testing across 1157 advanced ‘non-squamous’ patients 83% of
patients analysed following guidelines for EGFR, PD-L1 and ALK alterations (Royal
College of Physicians, 2020). Although, clinical data identifies 3.5% of non-squamous
patients present with ALK, which does not appear in adenocarcinoma patients
(Collison et al, 2014), questioning the rationale behind this. Across the 16.5% EGFR+
patients, 75% received treatment. Median survival was 216 days (Royal College of
Physicians, 2020). This is a slight improvement from the median survival of 203 days
(2011) (NICE, 2011). It could, therefore, be suggested novel therapeutics are an
essential clinical demand.
3.1 Futuristic treatmentapproaches: Personalised Pharmacogenomics
The current outdated and generalised histopathological and anatomical classification
into squamous or non-squamous should be updated in line with advancements of
genomic understanding and to introduce a personalised targeted approach for
adenocarcinoma patients. A logical solution suggested by TCGARN’s publication
was to characterise by point mutations (Collison et al, 2014), with additions of NF1,
STK11 and B-Raf (Collison et al, 2014) to Wilkerson et al’s TP53, K-Ras and ERBB1
suggestions (Wilkerson et al, 2012). Although, it could be suggested this is an
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incomplete solution with TCGARN stating copy number alterations, presented by
Figures 5 and 6, were not considered as pathogenesis driver alterations in their
publication (Collison et al, 2014). Potential futuristic approaches based upon
pharmacogenomic analysis of Figures 1-6 could include; Her-2, K-RAS, CDK-4/6,
PI3KCA and MET.
Reviewing Figure 7 suggests a clear issue with the treatment algorithm such as PD-
L1 negative patients treated with Atelozimub (anti-PD1 agent). It could be suggested
that directing this individual towards clinical trial testing could lead to a better
outcome. Furthermore, osimertinib is currently available towards EGFR+ patients
and this drug targets Her-2+ (National Institute for Health and Care Excellence,
2019). A critical and fundamental flaw across this protocol is the lack of personalised
genomic analysis, with Her-2 not possible to request by oncologists (Royal College
of Physicians, 2020). Shengwu et al suggest that Her-2 is the single direct
oncogenic driver for 6% of adenocarcinoma patients, but their breakthrough finding
was the Her-2 amplification acquisition as an underlying mechanism in the
resistance towards EGFR inhibitors (Shengwu et al, 2018). Mouse models indicated
monotherapy-osimertinib presented robust anti-tumour efficacy, suggesting a
potential alternative to the current “unmet clinical demand” (Shengwu et al, 2018).
Although, a previous phase II clinical trial by Gatzemeier et al indicated a poor
response to trastuzumab, with only 1.5 month increase in progression-free survival
(Gatzemeier et al, 2004). A potential flaw in the methodology was the requirement
for ‘untreated patients’ upon EGFR resistance findings (Shengwu et al, 2018).
Recently, Pillai et al’s trial stated patient group administered Her-2 targeted therapies
had median survival of 2.1 years against non-Her-2 therapies 1.4 year survival,
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suggesting further investigations (Pilla et al, 2017). Upon this, Ogoshi et al identified
that cells with co-contaminant Her-2 and K-Ras mutants do not respond to Her-2
targeted therapies, but results using neratinib against cell lines H2170 and Calu-3
cell lines led inhibition of proliferation, whilst , H1781 cell line indicated a strong
cytotoxic affect (Ogoshi et al, 2019). The current focus is upon phase II clinical trial
(NCT03845270) following prior CLEOPATRA breast cancer methodology using
trastuzumab, pertuzumab and docetaxel (Clinical Trials, 2019) could lead to
promising findings, with CLEOPATRA presenting 37% of patients alive after 8 years
(Swain et al, 2015). Similar to Her-2 amplification, Rehman et al state MET
amplification is another method by which EGFR resistance is acquired, highlighting a
key issue with MET progression by a severe lack of patients leading to a bottleneck
of trials (Rehman, & Dy, 2018). However, a potential solution, as highlighted prior, is
adenocarcinoma patients being grouped into ‘non-squamous’ and analysed for ALK
alterations (National Institute for Health and Care Excellence, 2019., Royal College
of Physicians, 2020 ). If positive, Crizotinib, a ALK/MET inhibitor is used (Chen,
Zhao, & Zhang, 2018), back-tracking adenocarcinoma patients receiving crizotinib
could produce relevant data. Although, critically, less than 1% of adenocarcinoma
patients possess ALK alterations (Collison et al, 2014).
Gopalan et al’s Phase II clinical trial (NCT01291017) using CDK-4/6 inhibitor
palbociclib in previously treated advanced patients (CDK2NA loss and wild-type
RB1) achieved stable disease in 50% of patients but did not affect overall
progression-free survival (Gopalan et al, 2017., Clinical Trials, 2016). Nie et al
suggested a similar finding to Her-2 findings, with palbociclib treated cells
overcoming EGFR resistance to afatinib, this could suggest combination therapy as
22. 22
a method of treatment whilst results are indicating this also reduces the risk of
relapse (Nie et al, 2019). Whilst, Thangavel et al identified novel findings with
palbociclib treated RB1-proficient cells suggested RB1-induced apoptosis,
suggesting the basis for a clinical trial (Thangavel et al, 2018). However, even with
this accumulating support for palbociclib, only one current trial (NCT02664935) for
lung adenocarcinoma is ongoing with 2021 completion (Clinical Trials, 2019-2).
Combination with, Gendicine, a recombinant adenovirus which expresses wild-type
P53 could prove beneficial, as off-label monotherapy has not yielded major results
(Zhang et al, 2017,. Chen et al, 2014., Ning, Sun, & Wang, 2011). A similar issue
with a lack of analysis can be seen with recent breakthrough treatment of a first
generation PI3KCA inhibitor, Alpelisib, which passed phase III breast cancer trials
presenting a 2-fold increase in progression-free survival (Andre et al, 2019). This is
currently being investigated by phase II clinical trial (NCT02276027) in NSCLC
adenocarcinoma patients but the clinical team are not publicly publishing results
(Clinical Trials, 2020). In relation to 86% of PI3KCA mutant patients presenting with
K-Ras or EGFR mutations, therefore, combination therapy could generate promising
results (Wang et al, 2014).
K-Ras mutants are highlighted clearly as a recurrent factor in the underlying
pathogenesis throughout Section 2. A critical issue arises with this common
alteration as no current targeted therapy is available. Recent breakthroughs by
Amgen produced AMG-510, the first K-Ras p.G12C mutant irreversible inhibitor in
clinical development, in pre-clinical testing (NCT03600883) patients remain on AMG-
510 after 42 weeks of use, presenting positive factors such as regression and
synergy with PD-L1 treatments (Canon, Rex, & Saiki, 2019). Upon these findings,
23. 23
AMG-510 has received fast tracking, with two clinical trials (NCT04185883 and
NCT03600883) utilising combination PD-L1 inhibitor:AMG-510 treatment and
monotherapy AMG-510 respectively (Clinical Trials, 2020-2., Clinical Trials, 2020-3).
This focus upon p.G12C links back to Jordan et al’s finding, supporting p.G12C as
the most common K-Ras mutant across both primary and metastatic patients
(Jordan et al, 2017). The promising initial results presenting greater survival in
comparison against the current, suggest AMG-510 as the most promising treatment
in clinical development. Although, in addition to the research areas suggested
throughout, further research into ATK-1 (novel MK-2206), FOSL-1 (novel LY-1816),
and the development of c-MYC inhibitors could lead to alternative promising
treatments in line with pharmacogenomic development (Jansen, Mayer, & Arteaga,
2016., Carabet, Rennie, & Cherkasov, 2018., Yang et al, 2019).
4.0 Conclusion to Review
Analysing copy number and point mutations across NSCLC adenocarcinoma patients
supports findings supporting the basis of adenocarcinoma as MAPK/PI3K/Cell cycle
pathway dysregulation, highlighting previously unappreciated alterations. The
development and introduction of patient personalised analysis is rapidly advancing to
provide targeted therapies to improve patient outcomes, with current EGFR and PD-
L1 analysis enabling targeted treatments leading to a median survival of 216 days
against 203 days without. Forthcoming developments correlate directly to
MAPK/PI3K/Cell cycles with K-ras, HER-2 and CDK-4/6 inhibitors presenting
promising findings. Suggested futuristic scope to improve early diagnosis,
personalised analysis and targeted treatments will lead to major increases in survival
rates.
25. 25
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