Basic research and clinical trials have confirmed that anti-epidermal growth factor receptor (epidermal growth factor
receptor, EGFR, also known as HER 1 or cerbB 1) therapy can improve the
traditional effect of chemotherapy drugs , and in some patients to
obtain a partial response rate and disease stabilization effect.
However, most patients do not benefit from this therapy , the reason is
that the performance of these patients eventually develop resistance
against EGFR therapy . This paper on the epidermal growth factor receptor tyrosine kinase inhibitor resistance mechanisms and research reviewed in the paper , providing a theoretical basis for clinical treatment .
An epidermal growth factor receptor and tyrosine kinase inhibitors and anti-tumor effect was first discovered EGFR HER / cerbB 1 transmembrane receptor tyrosine kinase family member of the family also includes HER 2 (cerbB 2), HER 3 (cerbB 3) and HER 4 (cerbB 4) [1]. Tyrosine kinase inhibitors (tyrosine kinase inhibitors, TKIs) are small molecule portion of quinazoline derivatives, ATP-competitive binding with the extracellular ligand -binding sites , blocking the tyrosine autophosphorylation of the molecule technology , inhibit EGFR activation , thereby inhibiting cell cycle progression , accelerated apoptosis, inhibition of angiogenesis , inhibition of tumor invasion and metastasis. Gefitinib (Gefitinib, also known as ZD1839 or Iressa) as third-line monotherapy for advanced non-small -cell lung cancer (non small cell lung cancer, NSCLC), erlotinib (Erlotinib, also known as the OSI 774 or Tarceva ) as a standard in the treatment of advanced NSCLC ineffective second-or third -line treatment drugs have made some clinical results [ 2,3 ] . However, not all studies have found that patients with high expression of EGFR on EGFR TKIs can respond to treatment , these studies also found that there are certain tumors Initial Gefitinib treatment response , but a few months later in the treatment of disease progression [ 4 ] , this indicates that there is a natural or secondary resistance to appear.
2 EGFR tyrosine kinase inhibitor resistance mechanisms
Because EGFR tyrosine kinase inhibitors via multiple intracellular signal transduction pathway regulates tumor cell proliferation , survival , apoptosis, metastasis, invasion and tumor-induced angiogenesis. Therefore, the dependence and non-dependent EFGR signal transduction in tumor cells , several different molecular mechanisms in cells resistant to EGFR inhibitors produce plays a very important role . These molecular mechanisms are the following :
2.1 Growth Factor Receptor signaling pathway bypassing
Genetic instability of tumor cells in drug -induced selective pressure, start another survival mechanism in order to prevent essential cell survival signaling pathway is inhibited primary . In these possible mechanisms , insulin-like growth factor receptor 1 (insulin like growth factor receptor 1, IGF 1R) activation is one of them . Chakravarti A , etc. [ 5 ] study found that for people who are sensitive glioblastoma multiforme (glioblatoma multiforme, GBM) cell lines , EGFR inhibitor AG1478 induced apoptosis reduce its invasion ; rather resistant GBM cell lines are showed increased levels of IGF 1R expression and activation of PI3K/Akt signaling pathway . Joint IGF 1R inhibitor AG1024 and AG1478 EGFR inhibitors significantly increased GBM cell lines resistant to apoptosis and reduce its invasiveness . In addition , Jones , etc. [ 6 ] studies have shown that breast cancer cells with Gefitinib -sensitive TAM R compared to Gefitinib -resistant subline TAM / TKI R breast cancer cells IGF 1R activation increased with IGF 1R TKI AG1024 treatment Gefitinib after increased sensitivity ; different breast cancer cell lines similar to the Gefitinib resistant subline DU145/TKI R prostate cancer IGF 1R activation increased. There are also studies [ 7 ] found that Gefitinib and IGF 1R inhibitor AG1024 when used alone can reduce several breast cancer cell lines (MDA468, MDA231, SK BR 3 and MCF 7) proliferation ; when combined application demonstrated on cell growth inhibition synergy. IGF 1R overexpression of SK BR 3 cell lines to Gefitinib resistance increased significantly. This suggests that , IGF 1R signal can be reduced to several breast cancer cell lines Gefitinib antiproliferative effect; in Gefitinib treatment, the increased resistance to IGF 1R target tissue Gefitinib than single drugs may be more effective . However Cappuzzo , etc. [ 8 ] by immunohistochemistry method 124 cases of Gefitinib in NSCLC patient study found that , IGF 1R expression with a natural resistance to Gefitinib not related .
2.2 Non- dependent EGFR activation-induced angiogenesis
Tumor cell -induced angiogenesis in maintaining local tumor growth, invasion and metastasis process plays an important role. EGFR autocrine pathway regulates vascular endothelial growth factor (vascular endothelial growth factor, VEGF) and basic fibroblast growth factor (basic fibroblast growth factor, bFGF) production. In allogeneic transplants who GEO colon cancer cells in nude mice , chronic administration of EGFR inhibitors (Gefitinib or Cetuximab) establish a GEO cells resistant subline . Initial EGFR inhibitors can inhibit tumor cell growth, through different incubation , the inoculation of tumor cells can be seen parts of the re-growth . In contrast, in EGFR and having the dual role of VEGFR 2 ZD6474 treatment, at up to 5 months of treatment period , the tumor cell growth is effectively suppressed . In addition, after giving Gefitinib or Cetuximab given ZD6474 can effectively inhibit tumor growth . Subsequent protein expression analysis showed that , compared with the parental cell line , resistant cell lines did not change expression levels of EGFR , VEGF expression levels increased by 5 to 10 times [ 9 ] . This suggests that EGFR TKIs secondary resistance is not due to the lack of EGFR expression , but because of the increased levels of VEGF expression . Therefore, the combined EGFR and VEGF drugs that target EGFR TKIs may be overcome resistance in an effective way . However , Taguchi , etc. [ 10 ] In an in vivo experiments, the same pair of Gefitinib and ZD6474 -sensitive cell lines compared to Gefitinib -resistant lung adenocarcinoma cell line (PC 9/ZD) is also a lack of sensitivity on the ZD6474 . This indicates that other non-dependent EGFR activation pathway is also involved in the biological resistance of tumor cells phenotype appears.
2.3 EGFR gene mutations and deletions targets
EGFR mutation caused the loss of EGFR expression and functional changes of tumor cells may also be EGFR tyrosine kinase inhibitor as a resistance mechanism . Blencke , etc. [ 11 ] found that in the EGFR tyrosine kinase domain with methionine instead of threonine 766 , can significantly reduce the growth inhibition of tumor cells to PD153035 sensitivity . Learn , etc. [ 12 ] found that 40% of glioma expression EGFRv Ⅲ, whereas expression of EGFRv Ⅲ GBM cell lines only at higher concentrations of Gefitinib , continuous exposure to lower its phosphorylation . This indicates that the cells expressing EGFRv Ⅲ Gefitinib has a relatively resistant .
An epidermal growth factor receptor and tyrosine kinase inhibitors and anti-tumor effect was first discovered EGFR HER / cerbB 1 transmembrane receptor tyrosine kinase family member of the family also includes HER 2 (cerbB 2), HER 3 (cerbB 3) and HER 4 (cerbB 4) [1]. Tyrosine kinase inhibitors (tyrosine kinase inhibitors, TKIs) are small molecule portion of quinazoline derivatives, ATP-competitive binding with the extracellular ligand -binding sites , blocking the tyrosine autophosphorylation of the molecule technology , inhibit EGFR activation , thereby inhibiting cell cycle progression , accelerated apoptosis, inhibition of angiogenesis , inhibition of tumor invasion and metastasis. Gefitinib (Gefitinib, also known as ZD1839 or Iressa) as third-line monotherapy for advanced non-small -cell lung cancer (non small cell lung cancer, NSCLC), erlotinib (Erlotinib, also known as the OSI 774 or Tarceva ) as a standard in the treatment of advanced NSCLC ineffective second-or third -line treatment drugs have made some clinical results [ 2,3 ] . However, not all studies have found that patients with high expression of EGFR on EGFR TKIs can respond to treatment , these studies also found that there are certain tumors Initial Gefitinib treatment response , but a few months later in the treatment of disease progression [ 4 ] , this indicates that there is a natural or secondary resistance to appear.
2 EGFR tyrosine kinase inhibitor resistance mechanisms
Because EGFR tyrosine kinase inhibitors via multiple intracellular signal transduction pathway regulates tumor cell proliferation , survival , apoptosis, metastasis, invasion and tumor-induced angiogenesis. Therefore, the dependence and non-dependent EFGR signal transduction in tumor cells , several different molecular mechanisms in cells resistant to EGFR inhibitors produce plays a very important role . These molecular mechanisms are the following :
2.1 Growth Factor Receptor signaling pathway bypassing
Genetic instability of tumor cells in drug -induced selective pressure, start another survival mechanism in order to prevent essential cell survival signaling pathway is inhibited primary . In these possible mechanisms , insulin-like growth factor receptor 1 (insulin like growth factor receptor 1, IGF 1R) activation is one of them . Chakravarti A , etc. [ 5 ] study found that for people who are sensitive glioblastoma multiforme (glioblatoma multiforme, GBM) cell lines , EGFR inhibitor AG1478 induced apoptosis reduce its invasion ; rather resistant GBM cell lines are showed increased levels of IGF 1R expression and activation of PI3K/Akt signaling pathway . Joint IGF 1R inhibitor AG1024 and AG1478 EGFR inhibitors significantly increased GBM cell lines resistant to apoptosis and reduce its invasiveness . In addition , Jones , etc. [ 6 ] studies have shown that breast cancer cells with Gefitinib -sensitive TAM R compared to Gefitinib -resistant subline TAM / TKI R breast cancer cells IGF 1R activation increased with IGF 1R TKI AG1024 treatment Gefitinib after increased sensitivity ; different breast cancer cell lines similar to the Gefitinib resistant subline DU145/TKI R prostate cancer IGF 1R activation increased. There are also studies [ 7 ] found that Gefitinib and IGF 1R inhibitor AG1024 when used alone can reduce several breast cancer cell lines (MDA468, MDA231, SK BR 3 and MCF 7) proliferation ; when combined application demonstrated on cell growth inhibition synergy. IGF 1R overexpression of SK BR 3 cell lines to Gefitinib resistance increased significantly. This suggests that , IGF 1R signal can be reduced to several breast cancer cell lines Gefitinib antiproliferative effect; in Gefitinib treatment, the increased resistance to IGF 1R target tissue Gefitinib than single drugs may be more effective . However Cappuzzo , etc. [ 8 ] by immunohistochemistry method 124 cases of Gefitinib in NSCLC patient study found that , IGF 1R expression with a natural resistance to Gefitinib not related .
2.2 Non- dependent EGFR activation-induced angiogenesis
Tumor cell -induced angiogenesis in maintaining local tumor growth, invasion and metastasis process plays an important role. EGFR autocrine pathway regulates vascular endothelial growth factor (vascular endothelial growth factor, VEGF) and basic fibroblast growth factor (basic fibroblast growth factor, bFGF) production. In allogeneic transplants who GEO colon cancer cells in nude mice , chronic administration of EGFR inhibitors (Gefitinib or Cetuximab) establish a GEO cells resistant subline . Initial EGFR inhibitors can inhibit tumor cell growth, through different incubation , the inoculation of tumor cells can be seen parts of the re-growth . In contrast, in EGFR and having the dual role of VEGFR 2 ZD6474 treatment, at up to 5 months of treatment period , the tumor cell growth is effectively suppressed . In addition, after giving Gefitinib or Cetuximab given ZD6474 can effectively inhibit tumor growth . Subsequent protein expression analysis showed that , compared with the parental cell line , resistant cell lines did not change expression levels of EGFR , VEGF expression levels increased by 5 to 10 times [ 9 ] . This suggests that EGFR TKIs secondary resistance is not due to the lack of EGFR expression , but because of the increased levels of VEGF expression . Therefore, the combined EGFR and VEGF drugs that target EGFR TKIs may be overcome resistance in an effective way . However , Taguchi , etc. [ 10 ] In an in vivo experiments, the same pair of Gefitinib and ZD6474 -sensitive cell lines compared to Gefitinib -resistant lung adenocarcinoma cell line (PC 9/ZD) is also a lack of sensitivity on the ZD6474 . This indicates that other non-dependent EGFR activation pathway is also involved in the biological resistance of tumor cells phenotype appears.
2.3 EGFR gene mutations and deletions targets
EGFR mutation caused the loss of EGFR expression and functional changes of tumor cells may also be EGFR tyrosine kinase inhibitor as a resistance mechanism . Blencke , etc. [ 11 ] found that in the EGFR tyrosine kinase domain with methionine instead of threonine 766 , can significantly reduce the growth inhibition of tumor cells to PD153035 sensitivity . Learn , etc. [ 12 ] found that 40% of glioma expression EGFRv Ⅲ, whereas expression of EGFRv Ⅲ GBM cell lines only at higher concentrations of Gefitinib , continuous exposure to lower its phosphorylation . This indicates that the cells expressing EGFRv Ⅲ Gefitinib has a relatively resistant .
However, a large
number of studies have shown that , EGFR tyrosine kinase domain
mutations in certain sites of the tumor cells increased sensitivity to
EGFR . Zhang et al [ 13 ] for the treatment of advanced NSCLC had EGFR
mutations in Chinese patients with right Gefitinb relationship between
reaction were studied . 98 patients, 12 patients had active gene
mutation , in which the Gefitinib -responsive patients , as well as non
-smoking , cancer, women with the mutation rate was higher than in
patients with mutations in patients without mutations to their overall
survival time long. Shimato , etc. [ 14 ] in patients with brain
metastases of lung cancer with EGFR mutations and the relationship
between the efficacy of Gefitinib was studied. Gefitinib treatment in 8
patients had brain metastases in NSCLC patients , 3 patients effective
treatment for patients with Gefitinib appeared tyrosine kinase domain of
EGFR mutations have emerged ( two cases of deletion mutations , one
case of point mutations ) , three cases were not found to have an
invalid mutation appears. This suggests that brain metastasis in NSCLC
Gefitinib efficacy of EGFR mutations with a certain relationship .
Takano , etc. [ 15 ] in 66 patients with recurrent NSCLC patients found
that 39 cases ( 59% ) patients with EGFR mutations ; among 20 patients
with exon 19 deletion mutation point performance ; 17 patients with exon
21 point appears missense mutation (L858R), 2 patients with exon 18
point appears nonsense mutation (G719S or G719C); wherein the EGFR exon
19 deletion in NSCLC patients given treatment with Gefitinib or
Erlotinib L858R point mutations in NSCLC compared with patients with a
longer survival time , response rates were 73 % and 50% ; progress in
better times were 24 months and 10 months. These studies suggest that it
is precisely because some sites EGFR domain mutations and deletions or
point mutations in the tumor cells become resistant to EGFR inhibitors .
2.4 EGFR downstream signal transduction pathway sustained activation
PTEN / MMAC / TEP (PTEN) phosphatase lack of functionality and continuous activation of Akt pathway resistant to EGFR inhibitors in the process also played a certain role.
PTEN is a lipid phosphatase and PI3K/Akt signaling pathways regulating tumor suppressor protein , PTEN loss of function causes excessive activation of Akt pathway , thereby increasing the cells resistant to apoptosis. Ueda et al [ 16 ] on three kinds of hepatocellular carcinoma cell lines (HCC3, CBO12C3, and AD3) and in vivo study found , Gefitinib inhibits all three cell lines Akt phosphorylation , but its inhibition AD3 cells effect has to be low , with HCC3 and CB012C3 cell lines compared , AD3 cells within the lower half of the concentration of PTEN ; using PTEN small interfering RNA (small interfering RNA, siRNA) cells were transfected HCC3 can reduce inhibition of these cells to Gefitinib sensitivity. Wang et al [ 17 ] reported that 40% to 50% of malignant glioma cells manifestations of PTEN , mammalian target of rapamycin body (mammalian target of rapamycin, mTOR) inhibitor rapamycin can increase PTEN deletion EGFR kinase inhibitors of tumor cells Erlotinib sensitivity. Combined EGFR / mTOR kinase inhibitors can inhibit U87MG and SF295 two kinds of malignant glioma cell lines tumor cell growth , while the downstream inhibition of PI3K signaling pathway has a cumulative effect . Therefore reconstruction PTEN function can re-establish the activation of Akt dependent EGFR signaling pathways , thereby restoring the sensitivity of these cells to ZD1839 . Although the reconstruction of PTEN function in tumor cells clinically difficult to implement , but the promotion of PTEN excessive activation of PI3K/Akt signaling pathway , and this activation by drugs regulation. Thus the use of PI3K/Akt pathway inhibitor LY294002 reduced PI3K/Akt pathway , EGFR activation can restore Akt signaling pathway , making MDA 468 cells with ZD1839 sensitivity [ 18 ] .
Continuous activation of the PI3K/Akt pathway in the process of resistance to EGFR inhibitors play an important role . Ihle , etc. [ 19 ] found that PI3 K signaling pathway inhibitors can increase the PX 866 NSCLC patients to EGFR inhibitors such as Gefitinib responsiveness. Gefitinib inhibition studies show that the height (SK BR 3), moderate (MDA MB 361) and low (MDA MB 468) 3 breast cancer cell lines of EGFR activation, but highly , moderately sensitive two P42/p44 MAPK and AKT activation was significantly reduced [ 20 ] . PI3K inhibitor LY294002 or MEK inhibitor PD98059 significantly inhibited MDA MB 468 cells growth. Consistent with this finding is : PD98059 and Gefitinib for MDA MB 468 cells have a synergistic effect , while the other two cell lines with a cumulative effect . Compared with monotherapy , both combination also makes MDA MB 468 cell lines increased apoptosis . This phenomenon is the same MAPK activation and BAD (ser112) phosphorylation decreased and associated with increased activation of AKT . This suggests that Akt anti-EGFR therapy may be one of the main resistance factors .
3 Others
Recent studies have found that carrying cyclin D1 (Cyclin D1) gene amplification and ( or ) protein overexpression of three cases of head and neck squamous cell carcinoma showed right Gefitinib resistance [ 21 ] . But with E cadherin transfected into cells for Gefitinib -resistant , can significantly increase the drug-resistant cell lines to Gefitinib sensitivity [ 22 ] . Therefore , histone deacetylase inhibitor MS 275 with Gefitinib may be overcome resistance to EGFR inhibitors in patients with lung cancer, a new drug therapies. In addition , the joint Gefitinib and to ErbB2 antibodies pertuzumab as a target body head and neck squamous cell carcinoma can provide incremental growth inhibition , this growth inhibition than single-use Gefitinib for Gefitinib -resistant HNSCC cell lines [ 23 ] . This study shows that EGFR / erbB family, other members of the EGFR is easier than on Gefitinib resistant .
In short, as a promising anticancer drugs , EGFR TKIs generation of secondary resistance is a difficult clinical problem solving . Current research indicates that a variety of molecular mechanisms involved in the resistance to the generation of these resistance mechanisms , combined some other targeted drugs may be a more effective tumor treatment.
2.4 EGFR downstream signal transduction pathway sustained activation
PTEN / MMAC / TEP (PTEN) phosphatase lack of functionality and continuous activation of Akt pathway resistant to EGFR inhibitors in the process also played a certain role.
PTEN is a lipid phosphatase and PI3K/Akt signaling pathways regulating tumor suppressor protein , PTEN loss of function causes excessive activation of Akt pathway , thereby increasing the cells resistant to apoptosis. Ueda et al [ 16 ] on three kinds of hepatocellular carcinoma cell lines (HCC3, CBO12C3, and AD3) and in vivo study found , Gefitinib inhibits all three cell lines Akt phosphorylation , but its inhibition AD3 cells effect has to be low , with HCC3 and CB012C3 cell lines compared , AD3 cells within the lower half of the concentration of PTEN ; using PTEN small interfering RNA (small interfering RNA, siRNA) cells were transfected HCC3 can reduce inhibition of these cells to Gefitinib sensitivity. Wang et al [ 17 ] reported that 40% to 50% of malignant glioma cells manifestations of PTEN , mammalian target of rapamycin body (mammalian target of rapamycin, mTOR) inhibitor rapamycin can increase PTEN deletion EGFR kinase inhibitors of tumor cells Erlotinib sensitivity. Combined EGFR / mTOR kinase inhibitors can inhibit U87MG and SF295 two kinds of malignant glioma cell lines tumor cell growth , while the downstream inhibition of PI3K signaling pathway has a cumulative effect . Therefore reconstruction PTEN function can re-establish the activation of Akt dependent EGFR signaling pathways , thereby restoring the sensitivity of these cells to ZD1839 . Although the reconstruction of PTEN function in tumor cells clinically difficult to implement , but the promotion of PTEN excessive activation of PI3K/Akt signaling pathway , and this activation by drugs regulation. Thus the use of PI3K/Akt pathway inhibitor LY294002 reduced PI3K/Akt pathway , EGFR activation can restore Akt signaling pathway , making MDA 468 cells with ZD1839 sensitivity [ 18 ] .
Continuous activation of the PI3K/Akt pathway in the process of resistance to EGFR inhibitors play an important role . Ihle , etc. [ 19 ] found that PI3 K signaling pathway inhibitors can increase the PX 866 NSCLC patients to EGFR inhibitors such as Gefitinib responsiveness. Gefitinib inhibition studies show that the height (SK BR 3), moderate (MDA MB 361) and low (MDA MB 468) 3 breast cancer cell lines of EGFR activation, but highly , moderately sensitive two P42/p44 MAPK and AKT activation was significantly reduced [ 20 ] . PI3K inhibitor LY294002 or MEK inhibitor PD98059 significantly inhibited MDA MB 468 cells growth. Consistent with this finding is : PD98059 and Gefitinib for MDA MB 468 cells have a synergistic effect , while the other two cell lines with a cumulative effect . Compared with monotherapy , both combination also makes MDA MB 468 cell lines increased apoptosis . This phenomenon is the same MAPK activation and BAD (ser112) phosphorylation decreased and associated with increased activation of AKT . This suggests that Akt anti-EGFR therapy may be one of the main resistance factors .
3 Others
Recent studies have found that carrying cyclin D1 (Cyclin D1) gene amplification and ( or ) protein overexpression of three cases of head and neck squamous cell carcinoma showed right Gefitinib resistance [ 21 ] . But with E cadherin transfected into cells for Gefitinib -resistant , can significantly increase the drug-resistant cell lines to Gefitinib sensitivity [ 22 ] . Therefore , histone deacetylase inhibitor MS 275 with Gefitinib may be overcome resistance to EGFR inhibitors in patients with lung cancer, a new drug therapies. In addition , the joint Gefitinib and to ErbB2 antibodies pertuzumab as a target body head and neck squamous cell carcinoma can provide incremental growth inhibition , this growth inhibition than single-use Gefitinib for Gefitinib -resistant HNSCC cell lines [ 23 ] . This study shows that EGFR / erbB family, other members of the EGFR is easier than on Gefitinib resistant .
In short, as a promising anticancer drugs , EGFR TKIs generation of secondary resistance is a difficult clinical problem solving . Current research indicates that a variety of molecular mechanisms involved in the resistance to the generation of these resistance mechanisms , combined some other targeted drugs may be a more effective tumor treatment.
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