IULIAN POPESCU, PhD, MD
The
Clinical Department of Radiobiology from the Fundeni Clinical Institute,
e-mail:
popdociul@yahoo.com
Alina Halpern, PhD, "Sf. Stefan" Hospital, Bucharest
Alina Halpern, PhD, "Sf. Stefan" Hospital, Bucharest
ABSTRACT
Since 2000 a new era has begun in the treatment of lung adeno-carcinoma
(ADC), which will improve, diversify, enrich the chemotherapy treatment of lung
cancer (PA) which becomes the targeted treatment for a heterogeneous disease. The
tyrosine-kinase inhibitors (ITK) have effect only upon ADC with EGFR mutations.
The most frequent mutations are at the level of the 19th exon through deletion and at the level of the 21st
exon through punctiform mutations
(T858R)
The EGFR and Kopi mutations, after the stimulation of ligands, undergo a
homo or heterodimerization, leading to the autophosphorylation of the ATP /
EGFR group, which in turn activate the pathways: PI3K/AKT, JAK/STAT and
Ras/MAPK which further lead to cellular growth, survival and proliferation. The
ITK blocks the ATP- EGFR phosphorylation, leading to the increase of cellular
apoptosis. But after a period
of treatment has emerged the resistance against ITK by the occurrence of the T790M mutation and the amplification of c-MET. These result in the activation of other signaling pathways, renewing the cell growth. This was possible due to the reversible connection of ITK with ATP- EGFR. In this manner have appeared the irreversible inhibitors, a further step in the treatment of this sub-set of ADC, which are currently being tested.
of treatment has emerged the resistance against ITK by the occurrence of the T790M mutation and the amplification of c-MET. These result in the activation of other signaling pathways, renewing the cell growth. This was possible due to the reversible connection of ITK with ATP- EGFR. In this manner have appeared the irreversible inhibitors, a further step in the treatment of this sub-set of ADC, which are currently being tested.
-----
Lung Cancer (LC) comprises two main
groups: non-small cell lung cancer and small cell lung cancer.
Within the non-small lung cancer we have 3 sets:adenocarcinoma (41-.43%),
squamous form (30%) and large cell
cancer.
In most of non-small cell tumors of the LC, the EGFR (epidermal growth
factor receptor) is highly expressed (2). This is associated with another
disorder of other signaling pathways, which furthers the tumor growth and affects
the prognosis.
Thus becomes rationally the therapy targeted with inhibitors tyrosine-kinases
(ITK) or anti-EGFR antibody therapy as Cetuximab (1)
The first
inhibitors of tyrosine-kinases have been gefitinib (Iressa) and erlotinib
(Tarceva).
They could have been implemented due to the effectiveness of their actions,
they are small molecule medications, reversible and have a low toxicity (2, 3).
The action of these 2 inhibitors of tyrosine-kinases has been outlined
between 2002-2004 (1, 4, 5, 6), which have demonstrated the association between
the EGFR mutations and the response to gefitinib treatment in non-small cell
lung cancer (4, 5, 6)
THE EGFR MUTATIONS
In genes and chromosomes, which usually are steady, sometimes occur sudden
changes, which are called mutations. These mutations happen either to a single
gene or to the chromosome change. Mutations lead to acquiring some functional
properties. They are most frequently found in non-small cell lung cancer and
rarely in ovary cancer, colon cholangiocarcinoma (4).
The function of 2 ITK is possible only in case of emergence of mutations in
EGFR level. Mutations increase the susceptibility to the treatment with ITK,
leading to cell death (1, 7, 8). The G719S and L858R point mutations, as well as deletion mutations at the level
of exon 19 are associated with sensitivity to the action of tyrosine-kinase
inhibitors.
Mutations by insertion in the exon 20 are
associated with the primary resistance. Instead the T790M point mutation is a secondary
mutation and is associated with resistance to tyrosine-kinase inhibitors.
Location.
The EGFR mutations appear between the exon 18 and exon 21. There are two
types of mutations:
·
through
deletions in exon 19 in a percentage of 45%;
·
by
point mutation in exon 21 in a percentage of 40% (L858R).
The most common are in the exon 19 (9).
Frequency.
The mutation frequency prevailed in East Asians 30-40% and in Europeans
10-15% (8-5), and according to other authors was between 25-50% in East Asians
and 10% in Europeans and USA Americans (7). No one knows the cause of this difference.
Mutations are more frequent in women, non-smokers and lung adenocarcinoma
(10).The frequency of mutations prevail in adenocarcinoma 53% (115 cases out of
215).
In adenocarcinoma
the mutations have been connected with:
non-smokers 74% (83 cases out of 111);
women 66%
(87 cases out of 131) (11).
The
histologic differentiation was:
well differentiated 63%(55 cases
of 86);
poorly differentiated 31% (11 cases
of 41).
The mutation
frequency drops with the increase in the number of cigarettes:
non-smokers 74,8%;
passive smokers 61,1%;
ex- smokers 35,7%;
active smokers 19%.
Also,13% have been double mutations (11).
Ligand binding to EGFR stimulates the
autophosphorylation and activation of signaling by promoting both cell
proliferation (via MAPK-ERK) and survival (via AKT-STAT). Comparing with the
wild type, the mutant receptors preferentially activate survival pathways and
their inactivation by tyrosine-kinase inhibitors removes the survival signals on
which they have become dependent.
Further, altering the other signaling pathways downstream, the EGFR
mutations are inside the binding place with the ITK and increase the inhibition
of receptor activation.
The EGFR mutations mechanism of action
Tumors with EGFR mutations are dependent on the EGFR signaling for growth,
survival and proliferation (2,12).
The EGFR protein is a member of the Erb tyrosine-kinase family. Along with
the EGFR protein, ErbB2 (HER2) and ErbB3 play an important role.
After ligands stimulation, the EGFR undergoes a homo or heterodimerization,
leading to autophosphorylation of the ATP / EGFR group. Other intracellular signaling
proteins are further activated (10, 13).
There are several signaling pathways that activate and include the
following pathways: Ras/MAPK, PI3K/AKT, JAK/STAT (10, 13). Their activation lead
to cellular growth, survival, proliferation.
To this mechanism also contribute ErbB2 (Her2) and ErbB3.
ErbB2 (Her2). Connecting Her2 with EGFR mutations raises the ErbB3 signaling
(10). Also Her2 predicts the sensitivity
in treatment with ITK in cancer with EGFR mutations (10-14 )
ErbB3 is tyrosine-kinase phosphorylated and contributes to the activation
of secondary signaling pathways (down-streams) in cancers sensitive to the
treatment with ITK / EGFR. To this experiment has been observed a correlation
between sensitivity to ITK and ErbB3 expression (10, 15, 16, 17).
The mutations presence, activation of signaling pathways (PI3K-AKT),
association of ErbB2 (Her2) with EGFR mutations and ErbB3 expression - all
increase the sensitivity to the treatment with ITK-EGFR.
In reality however there are lung cancers in which EGFR do not control
these pathways, which makes the use of ITK to become ineffective. These other
pathways lead to activation of secondary signaling pathways making ITK treatment
ineffective and thus drug resistance arises.
THE EGFR COPIES (AMPLIFICATION)
Together with the EGFR mutations study, it has been achieved to obtain the
number of copies of the EGFR gene. This has become possible with the emergence of
FISH method (fluorescence in situ hybridisation) which highlights the number of
copies of the EGFR gene (1, 19).
These data
have been correlated with the increasing sensitivity in ITK(1, 19, 20).
A high number
of copies is deemed starting from 3 or more copies.
Linking the number of copies with EGFR mutations increases the response to
the treatment with ITK. Thus:
- FISH-positive patients (high number of
copies) had an increase of survival after treatment with ITK, compared to placebo
(1, 21, 22)
The ONCOBEL research showed that 67%
of tumor samples have been FISH positive (1, 23). The presence of amplification
by increasing copies number, along with mutations raise the proportion of
positive results after treatment with ITK.
RATE of response to treatment with ITK is higher in FISH-positive patients
compared to the negative FISH (68% compared to 9,1%) (24)
TIME FOR THE absence of tumor
progression is longer in FISH-positive
patients (7.6 months) than in FISH-negative ones (2.7 months) (1, 4, 25).
The copy number enhancement together with the EGFR mutations in patients
with non-small cell lung cancer treated with gefitinib led to the a favorable
result of 82% compared to the control group of 11%.
The survival has been 20.4 months in those with EGFR mutations and copies and
6.9 months in the control group (4, 26).
The EGFR mutations and high number of copies are associated with better
clinical outcomes in those treated with gefitinib (4,25). Generally copies are
a absence time forecaster for the tumor progression (4).
ITK/EGFR TREATMENT RESISTANCE
In cancers
with EGFR mutations, if EGFR are inhibited through ITK, the activation of
EGFR-dependent signaling pathways will be stopped. The cancer cell reaction is
to look for other ways to maintain its activity and thus resistance occurs.
Long-term
administering (8-9 months up to 1-2 years) leads to a secondary resistance,
clinically displayed by relapse or tumor progression (1, 27).
The mechanism
of secondary resistance:
1)A SECONDARY
T790M MUTATION APPEARS (1, 28, 29). It occurs at the level of exon 20 (1). This
secondary mutation affecting the reversible connection between ITK and ATP /
EGFR group and makes it inefficient (1, 10, 30, 31, 32). The emergence of
resistance is explained by the fact that
the T790M mutation affects the reversible connection between ITK and the ATP- EGFR
group and thus is maintained the activity of downstream signaling pathways.
Only the continuance of PI3K/AKT pathway activity is sufficient to produce resistance
to ITK (10, 33, 34, 35). The acquired resistance is linked to the secondary
mutation which leads to the substitution of methionine for threonine in
position T790M (10, 36). Now we have a secondary resistance, which is made through
a 2nd degree mutation in other sites (36).
In exon 21 has also been noticed an adenine substitution for threonine at
position 854 (T854A), which inhibits the EGFR-ATP phosphorylation (36).
In persons showing ITK treatment resistance the T790M secondary mutation is
observed in a percentage of 50% (1, 9, 27). The presence of T790M mutation is
the most common, although other mutations have also been found in exon 19-21
(1, 36, 37; 38).
The T790M mutation is noticed in women, nonm-smokersfumători and those
having mutations through deletions (1).
2) The second major mechanism for
the occurrence of secondary resistance is the c-MET oncogene amplifying. It was
seen in 20% of patients with secondary resistance to treatment with ITK-EGFR
(1, 10, 32, 33, 36, 39).
C-MET is a tyrosne-kinase receptor .
The c-MET amplifying activates by using ErbB3 the PI3K pathway
independently of EGFR action. This allows the downstream signaling pathways (EGFR-dependent)
to continue their activity despite the presence of ITK-EGFR (1, 40).
The MET amplifying appears independently of the T790M mutation presence, although
they may also be simultaneous (1, 39,
40).
The c-MET amplifying causes resistance by activating the PI3K-AKT pathway
dependent on ErbB3 (39). By inhibiting the c-Met amplification can be restored the ITK sensitivity (42).
Thus cancerous tumors which have become resistant to treatment with ITK
through secondary mutations are dependent on kinase activation, leading to cell
proliferation.
Fig. 5. The
EGFR signaling in mutations of non-small cell lung cancer in patients with
sensitivity or resistance to treatment with tyrosine-kinase inhibitors of EGFR
A) EGFR phosphorylates ErbB3 in order to activate in
patients with non-small cell lung cancer
and sensitive to the treatment with Gefitinib or Erlotinib. In such
cancers, following the treatment with gefitinib or erlotinib, the EGFR, ErbB3 and
AKT phosphorylation stops.
B) Gefitinib or
Erlotinib are unable to inhibit the EGFR phosphorylation in the presence of T790M EGFR mutation. The EGFR signaling persists
in the presence of Gefitinib or Erlotini, leading to the persistence of ErbB3
and AKT phosphorylation.
C) c-Met may also
activate the PI3K-AKT signaling through ErbB3. In patients with non-small cell
lung cancer, along with the c-MET amplification, gefitinib or Erlotinib can continue
to inhibit the EGFR phosphorylation, but not the ErbB3 phosphorylation. This leads
to a persistent activation of PI3K-AKT signaling via ErbB3 in a way independent
of EGFR.
D) Other possible
mechanisms in resistance to gefitinib or Erlotinib.
These potential mechanisms
include alternative pathways for maintaining the PI3K-AKT signaling, either
through the PI3K oncogene and by other kinases receptors that can activate the
PI3K-AKT signaling in a way independent of ErbB3. In those cases Gefitinib or
Erlotinib may inhibit EGFR and ErbB3 phosphorylation, but not also AKT phosphorylation
(P. S. Hammerman, Past A. Janne Bruce, E. Johnson - Clinical cancer
research 2009; 15/24 : 7502)
The Kras MUTATIONS
Mutations in codons 2, 12, 13 and 63 lead to the activation of ras protein
and allows the cancer cell to grow irrespective of EGFR signaling and makes it
resistant to the treatment with ITK-EGFR (1, 43).
In lung cancer 95% of the Kras mutations are found in
codons 12 and 13 (43).
The Kras mutations in smokers appear by transversion (changing a purine
with a pyrimidine and vice versa (G—T, G—C) (43, 44). The transversion ethiology G—T in patients with
lung cancer is related to the the carcinogenic effect of cyclic aromatic
hydrocarbons from tobacco (43, 44, 45)
The G—T transversion is not frequent
in the adenocarcinoma with EGFR mutations. Instead the presence of Kras mutations
in non-smokers is performed through transition (a purine is changed with other
purine or a pyrimidine with other pyrimidine (G—A).
The Kras oncogene mediates an alternative mechanism by activating the
PI3K/Akt pathway.
Activation of each gene leads to abnormalities in common signaling (43).
The frequency of KRAS mutations in ADC was 9.7% (21 of 215 patients) and
was associated with smoking and histological grading, namely in the low differentiated
form (43).
Kras mutations
represent:
15% in non-smokers;
22% in ex-smokers;
25% in active smokers.
Kras mutations are found in 25% of persons in Europe or USA and are rarely
found in Eastern Asia. (1, 46).
Kras mutations increase in frequency in smokers with ADC and are rare in
non-smokers ADC (43, 47).
Kras
mutations are significantly correlated with : gender, age and smoking history (1,
43).
Kras mutations are resistant to the treatment with ITK-EGFR inhibitors (1,
36, 43) and following the treatment with adjuvant chemotherapy have a weak
response as concerns the survival (43).
The Kras
mutations are exclusive with EGFR mutations (1, 11, 48,
49).
Concerning the results of the treatment, we distinguish:
a) Patients with Kras mutations - no benefit after the treatment with ITK-EGFR.
b) Patients without Kras mutations ( Kras wild) have a gain regarding
survival (1, 22).
Patients with Kras mutations treated
with ITK have a lower survival than those treated with chemotherapy (1, 50).
The Kras mutations do not change the absence time of disease progression,
but affects the overall survival, while EGFR mutations extend the absence time
of disease progression compared with the wild EGFR genes (1, 51).
The Kras mutations as well as EGFR mutations have the ability to predict
what would be the result following the treatment with ITK / EGFR or resistance to
this treatment (1, 46, 51)
IRREVERSIBLE EGFR INHIBITORS
The occurrence of resistance - after a period of time - the treatment with
inhibitors of the tyrosine-kinases made necessary the appearance of other
substances to keep the favorable action, but to avoid the development of
resistance.
Thus have appeared the irreversible inhibitors of tyrosine kinases.
1) PELITINIB
(RRB-569)
The action target is EGFR. The maximum tolerated dose is 75mgr. Adverse
reactions: diarrhea, nausea, rash.
Pelitinib links to EGFR, ErbB2 and ErbB4 covalently, irreversibly,
inhibiting the EGFR phosphorylation and signal transduction, leading to
apoptosis and suppress of the tumor proliferation which indicate over
expression of these receptors (1, 52).
2) CANERTINIB (CI-1033).
Is a pan-Erb-tyrosine.kinase inhibitor. It is active on the 4 Erb members.
Targets the EGFR and, by irreversibly inhibiting the signaling functions of transduction,
the apoptosis and suppression of proliferation occurs (1, 40).
3) AFATINIB (BIBW2992)
This is an irreversible inhibitor, aiming at EGFR and ErbB2(Her2). Through its
action increases the time of tumor progression absence up to 14 months. Instead,
the response rate is 58% and tumor reduction to 61%. T854A mutation can be overcome
by administering BIBW 2992 (36)
4) XL647
It is a potent inhibitor of tyrosine-kinases receptor, which are involved
in tumor proliferation and tumor vascularization (EGFR, Her2, VEGF).
The dose was of 350mgr,
for 5 days in 14 cicles. Adverse reactions: rash, diarrhea, nausea.
Clinical
improvements have been obtained (40).
5) PF-00299801.
It is a potent inhibitor of the EGFR mutations with T790M. It is effective
in cancers with mutations or amplification of ErbB family members. It is an
inhibitor of both wild ErbB2 and of ErbB2 mutation resistant to the treatment with
ITK-EGFR (44, 54).
IRREVERSIBLE INHIBITORS OF c-MET
1) MET-MAB
Is a single monovalent antibody that binds to the c-Met receptor and
prevents the fixing of hepatocyte growth factor on the Met receptor, which in
turn blocks the receptor stimulation and thus inhibits the MET signaling pathway,
(which can be activated in cancer).
Met-Mab combined with erlotinib in patients with non-small cell lung cancer
improves both the time of disease non-progression and the overall survival.
Patients have
been divided into 2 groups:
- the first group has shown a high MET level,
- the other
group shows a low level of MET. The dose was 15mgr/kg.body and intravenous
administering.
The patients with overexpressed Met responded favorably – to the treatment
with MED-MAB and Erlotinib having the survival time without disease progression
of 12 weeks compared with those treated only with erlotinib or those with placebo
only 6.4 weeks.
In patients with low MET expression, the result was very poor in all 3
combinations (55).
2) ARQ 197has small molecules and activates on
MET (1);
3) XL184. Its targets are Erb, MET, VEGFR2
(1).
The elements that predict the response to treatment with ITK are:
1) from
the clinical point of view: female gender, non-smokers, East Asians.
2) from the anatomopathological point of
view:
b) poor differentiated adenocarcinoma (with Kras mutations).
3) in
terms of mutations:
b) point mutations in exon 21: L858R mutations.
4) in
terms of location:
a) location in the central bronchi areas;
adenocarcinoma with KRAS mutations;
b) location in peripheral areas -
adenocarcinoma with EGFR mutations.
PRACTICAL CONCLUSIONS
1) The treatmentul with tyrosine-kinases inhibitors
should be consideredt the first option in people with EGFR mutations;
2) The test of EGFR mutations, of EGFR copies
(amplification) and of Kras mutations is compulsory in the treatment of lung
adenocarcinoma with EGFR inhibitors of tyrosine-kinases.
3) In small cell lung cancer most patients do not show EGFR mutations (1).
GLOSSARY
CODON: a sequence
of three adjacent nucleotides constituting the genetic code and specifying the
structural position of an amino acid in the polypeptide chain during the protein
synthesis.
DELETION: chromosome
aberration consisting of partial or total loss of an arm of a chromosome.
DIMER: a chemical
structure consisting of two identical subunits (monomers).
EXON: is a sequence
of nucleic acid.
TRANSDUCTIONS:the transfer
of a genetic information from a cell to another through one vector.
TRANSCRIPTION: stage
of a gene expression during which the information contained in a DNA sequence
is copied in the form of a RNA sequence.
AKT/PKB: is a
serin-threonin protein kinase. Plays a role in cell proliferation, apoptosis,
transcription and cell migration.
ERK: extracellular
signal-regulated kinases.
JAK: is a
protein-kinase (Janus Kinase).
PI3K: Phosphoinositide3-kinase plays an important
role in many cellular functions. One effect of the PI3K is AKT. The AKT activation
leads to phosphorylation and regulation of the kinases, transcription factors activity
and other regulatory molecules.
STAT: the Signal
Transducers and Activation of Transcription protein.
BIBLIOGRAPHY
1) J. Cadranel, G.
Zalcman, L. Seqiist: Genetic
profiling and epidermal growth factor receptor-directed therapy in nonsmall
cell lung cancer. Eur. Resp. J. 2011; 183-193;
2) Fred R. Hirsch,
M. Varella-Garcia, Rafal Dziaddzusko R.et al: Fluorescence in situ
hybridisation sub group analysis of
TRIBUTE, a phase III trial of Erlotinib plus Carboplatin and Paclitaxel
in no small cell lung cancer Cl.
Can. Res. 2008; 14:6317-5323;
3) Perez-Soler R.: Phase
II clinical trial data with the epidermal growth factor receptor tyrosine
kinase erlotinib(OSI-774) in non small cell lung cancer. Clinic. Lung
Cancer 2004, 6 Suppl.: S20-3;
4) L. V. Sequist,
Daphe W. Bell, Thomas J. Lynch: Moleculars Predictors of response to
Epidermal Growth Factor receptor Antagonist in non small cell lung cancer. J.
of Clinical Oncology 2007; 25:587-595;
5) Lynch T. J.,
Bell D.W., Sardella R. et al: Activating
mutations in the epidermal growth factor receptor underlying responseness of
non small cell lung cancer to gefitinib. N. Eng. J. Med. 2004;
350:2129-2139;
6) Paez J.G., Janne P.A., Lee J.C. et al: EGFR mutations in lung can er corelation
with clinical response to gefitinib therapy.
Science 2004; 304:1497-1950;
7) Takano T., Ohe
Y., Sakamoto M. et al: Epidermal growth factor receptor gene mutations and
inceased coppy numbers predict gefitinib sensitivity in patients with recurrent
non small cell lung cancer. J. of
Clinical Oncolgy 2005;
23:6829-6837;
8)Han S. W., Kim
T.Y., Hwang P.G. et al: Predictive and prognostic impact of epidermal growth
factor receptor mutations in non small cell lung cancer patientstreated with
gefitinib. J. Clin. Onc. 2005; 23:2493-2501;
9) Takayuki
Akosaka-Yasushi, Yatabe Hideki Endow: Analysis of Epidermal growth factor
receptor gene mutation in patients
with non small cell lung cancer and
aquired resistance to gefitinib. Clin.
Cancer Resarch 2006; 17:5764-5709;
10) Peter S. Hammerman, Past A
, Bruce E. Johnson: Resistance to epidermal growth factor receptor
tyrosin-kinase inhibitors in non small cell lung cancer. Clinical cancer
research 2009; 15:7508-7509;
11)
Issaw Yee San Tam, Lap Ping Chung, Wai Sing Shen et al: Distinct Epidermal Growth Factor Receptor and KRAS Mutation
Patterns in Non–Small Cell Lung Cancer Patients with Different Tobacco Exposure
and Clinicopathologic Features. Clin Cancer Res March 1,
2006 12:1647-1653;
12) Bell D.W.,
Lynch T.J., Hasserlat: Epidermal growth factor receptor mutations and gene
amplification in non small cell lung cancer:molecular analhysis of the
IDEAL/INTACT gefitinib trials J. of
Clinical Oncology 2005; 23:8081-8084;
13) Holbro T.,
Civenni G., Hynes N.F.: The ErbB recepors and their role in cancer
progression Exp. Cell. Res. 2003; 284:93-110;
14) Engelman J.A.,
Janne P.A., Mermel C. et al: ErbB3 mediates phosphoinositide 3-kinase
activity in gefitinib sensitive non small cell lung cancer cell leines. Proc. Natl. Acad. Sci. USA 2005;102:3788-3793;
15) Sordella R.,
Bell A. W., Haberd. A. Settleman J. et al: Gefitinib sesitizing EGFR
mutations in lung cancer activate anti[apoptotric pathway. Science 2004;
305:1163-1167;
16) Tracy S.,
Mukohara T., Hansen M. et al: Gefitinib induced apoptosis imn the EGFR/L858R
non small cell lung cancer cell-line H3255. Cancer Research 2004;
64:7241-7244;
17) Weinstein I.B.: CANCER Addiction to oncogenes-the
Achhiles Heal of cancer. Science 2002; 297:83-84;
18) Fujimoto N.,
Wislez N. M., Zhang J. et al: High expression of ErbB familiy members and
their ligands in lung adenocarcinomas that are
sensitive to inhibition of
epidermal growth factor receptor. Can. Researc. 2005; 65:11478-11485;
19) Capuzzo F.,
Hirsch F.R. ,Rossi E. et al: Epidermal growth factor receptor gene and
protein and gefitinib sensitivity in non small cell lung cancer. J. Natl.
Cancer Inst. 2005;97:643-655.
20) Tsao M. S.,
Skurada A., Cutz J. C. et al: Erlotinib in lung cancer-molecular and
clinical predictions of out-come. N. Eng. J. Med. 2005; 32:135-134;
21) Hirsch
F.R.,Varella Garcia M., Bunn P.A. junior et al: Molecular prediction of
out-come with gefitinib in a phase3-placebo controlled-study in advanced non
small cell lung cancer. J. Clin. Oncology 2006; 24: 5034-5042;
22) Zhu C.Q., da
Cunha Santos G., Ding K. et al: Role
of Kras and EGFR as boi-markers of response to erlitinib in National Cancer
Institute of Canada clinical Trial Group Study Br. 21. J. of
Clin. Oncology 2008; 26:4268-4271;
23) Capuzzo F.,
Ligorio C. Janne P. A. et al: Prospective study of gefitinib in
epidermal growth factor receptor,fluorescence in siti hybridisation-positive
phospho-AKT positive in never smoker patients with advanced non small cell lung
cancer. The Oncobel Trial; J.
of Clinical Oncology 2007; 25:2248-2255
24) Niho S., Kubota
K., Goto K. et al. First-line single
agent treatment with gefitinib in patients with advanced non smll cell lung
cancer. A phase II study. J. of.
Clin. Oncology 2006; 84-89;
25) Douillard J.,
Shepherd F., Hirsch V. et al: Molecular
predictors of out come with gefitinib and docetaxel inpreviously treated non
small cell lung cancer: data from the radomized Phase III INTEREST trial. J. of
Clin.Oncology 2010; 28:744-752;
26) Takano T., Ohe
Y., Sakamoto H. et al: Epidermal
growth factor receptor gene mutations and increased copy numbers predict
gefitinib sesitivity in patients with recrrent non small cell lung cancer. J.
of Clin Oncology 2005; 23:6829-6837;
27) Sequist L.V.,
Lynch T.: EGFR tyrosine kinase inhibitors in lung cancer: an evolving story Annu.
Rev. Med. 2008; 59:429-442;
28) Balak M. N.,
Gong Y., Riely G. J. et al: Novel
D76Y and common secondary T790M mutations in epidermal growth factor
receptor-mutated lung adeno [carcinomas with aquired resistance to kinase
inhibitors]. Cli. Can. Rsearch 2006;12:6494-6501;
29) Pao W., Miller
V.A.: Epidermal growth factor receptor mutations,small-molecule kinase
inhibitors nand non small lung cancer: current knowledge and future directions. J. of
Clin. Oncology 2005; 23:2556-2568;
30) Yun C. H.,
Mengwasser K. E., Tom A. V. et al: The T790M mutation in EGFR kinase causes
drug resistance by increasing the affinityb for ATP. Proc. Natl. Acad. Sci.
USA 2008;105:2070-2075;
31) Fujimoto N.,
Wislez M., Zhang J. et al: High
expressionb of ErbB familiy members and their ligands in lung adeno-carcinomas
that are sensitive to inhibition of epidermal growth factor receptor. Cancer
Research 2005; 65;11478-11485;
32) Capuzzo F.,
Varella-Garcia M., Shigematsu H. et al: Inceased Her2 gene copy number is
associated with response to gefitinib therapy in the epidermal growth factor
receptor-positive nonsmall cell lung cancer.
J. of Clin Oncology 2005;
23:5007-5018;
33) Wang S.E., Narasanna A., Perez-Torres et al: Her2
kinase domain mutation results in consitutive phosphorylation of Her2 and EGFR
and resistance to EGFR tyrosine–kinase inhibitors. Cancer Cell
2005;10:25-38;
34
)Subramanian J. J., Govindan R.: Molecular
genetics of lung cancer in people who have never smoked. Cancer Oncol 2008;
9:676-682;
35) Ellis I. M.,
Hicklin D. J.: Resistance to targeted therapies:refining anti-cancer therapy
in the era of molecular oncology. Clin. Can. Research 2009;15:7471-7478;
36) Bean J., Riely
G. J., Balak M.: Aquired resistance to epidermal growth factor receptor
kinase inhibitors associated with a novel T854A mutation in a patient with EGFR
mutant Lung carcinoma. Clin. Can. Research 2008; 14:7519-7525;
37) YANG C. J.,
Chao T. J., Shin J. et al: Use of BIBW2992 a novel irreversible EGFR KTI to
induce regression in patrients with adenocarcinoma of the lung and acivatinf
EGFR mutations: preliminary results of a single arm phase II clinical trial. J.
of Clinical Oncology 2008; :8026-;
38) Kobayashi S.,
Boggon T.J., Dayaram T. et al: EGFR mutations and resistance on non small
cell lung cancer to gefitinib. New. Engl. J. Med 2005; 352:786-792;
39) Engelman J.A.,
Zengmullahu K., Mitsudani T. et al: Met amplication leads to gefitinib
resistance in lung cancer by activating ErbB3 signaling. Science 2007; 316:1039-1043;
40) Janne P.A., von
Pawel J., Cohen R.B. et al: Multicenter, radomized, phase II trials of
CI-1033 on irreversible pan-ERBB inhibitor, for previously treated advanced non
small cell lung cancer. J. of.
Clinical Oncology 2007; 25:3936-3944;
41) Bean J.,
Brennan C., Shin J. Y. et al: MET
amplification occurs with or without T790M mutations in EGFR mutant lung tumors
with aquired resistance to gefitinib or erlotinib. Proc .Natl. Acad. Sci.
USA 2007; 104:20932-20937;
42) Pantaleo, M.
A., Nannini M. A., Maleddu et al: Experimental result and related
implcations of PET detection of epidermalgrowth factor receptor (EGFR) in
cancer. Annals. Oncol. 2009; 20:213-226;
43) Riely G. J.,
Kris M. G., Rosenbaum D. et al: Frequence
and distinctive spectrum of Kras mutations in never smokers with lung
adenocarcinoma. Clin. Can. Research 2008;14:5731-5734;
44) Engelman J. A.,
Zejnullahu K., Mitsubomi T.: MET
amplification leads to gefitinib resistance in lung cancer by activating ERBB3
signaling. Science2007; 316:1039-1045;
45) Jie Oi, Michele
A. Metigue, Andrew Rogers: Multiple mutations and bypass mechanism can
contribute to dev elopment of aqiuired
resistance to MET inhibitors Cancer Research 2011;71:1081;
46) Pao W.,
Wang T. Y., Riely T. J., et al: Kras
mutation and primary resistance of lung adenocarcinomas to gefitinib or
erlotinib. PloS MED 2005;2;e1;
47) Nelson H. H.,
Christiani D. C., Mark E. J.et al Implications
and prognostic value of Kras mutations for early-stage lung cancer in
women. J. Natl. Cancer Institute
1999; 91:2032-2038;
48) Kosaka T.,
Yatabe Y., Endoh H. et al: Mutation
of the epidermal growth factor receptor
gene in lungcancer: biological and clinical implications. Cancer Research
2004; 64:8915-8923;
49) Tam I. Y.,
Chung I. P., Suen W. S. et al: Distinct epidermal growth factor receptor and
Kras mutation patterns in non small cell lung cancer patientst tobacco exposure
and clinico-pathologic features. Clin. Can.Research 2006;12:1647-1653;
50) Eberhard D. A.,
Johnson B. E., Amler L. C. et al: Mutations in the epidermal growth
factormreceptor and in Kras are predictive and prognostic indicators in
patients with che, motherapy alone and in combination with erlotinib. J.
of Clin. Oncology 2005;23:5900-5909;
51) Cadranel J., Lizard S., Mauguen A. et al: Impact of clinical and biological markers
on progression-free survival (PFS) and overal survival in patients (pts) with
adanced non small cell lung cancer (NSCLC) treated by erlotinib results of the
ERMETIC cohort. www.meet.ics.com/wcl2009/pdf/Posterdiscussion
Session-sunday 2 AUGUST 2009.PDF. Data last accessed September 30, 2010.
Date last updated:August 2, 2009;
52) Charles
Eichman, Manuel Hidalgo, Joseph P. Boni et al: Phase I study of EKB-569 an
irreversible inhibitor of the epidermal growth factor receptor in patients with
advanced solid tumors. J. of Clin.
Oncology 2006;24/15:2252-226;
53) Dr. Shiris
Gadgeel: Post abstract P3-134. The 12
international association for the study of lung cancer. World conference of
lung cancer Seoul, South Korea;
54) Gonzales A. J.,
Hook K. E., Althaus I. W. et al: Anti-tumor activity and pharmacokinetic
properties of PF-00299804, a second generation irreversible pan ErbB receptor
kinase inhibitor. Mol. Cancer Therap. 2008, 7:1880-188;
55) Roxanne
Nelson: METMAB added to erlotinib
improve survival in a subset of patients with
Lung Cancer. MEDSCAPE MEDICAL NEWS 2010 oct 9, Milan, Italy.
Niciun comentariu:
Trimiteți un comentariu