EGFR抑制剂(谷风研究)
合集下载
相关主题
- 1、下载文档前请自行甄别文档内容的完整性，平台不提供额外的编辑、内容补充、找答案等附加服务。
- 2、"仅部分预览"的文档,不可在线预览部分如存在完整性等问题,可反馈申请退款(可完整预览的文档不适用该条件!)。
- 3、如文档侵犯您的权益，请联系客服反馈,我们会尽快为您处理(人工客服工作时间：9:00-18:30)。
No extracellular domain Ligand cannot bind
TK constitutively active
EGFR – Wild Type
PFra Baidu bibliotekesent Can bind TK activated by ligand binding
Cannot dimerise
Can dimerise
9
EGFR Stimulation & dimerisation
TK
TK
TK
TK
EGFR Homo Dimerisation
erbB1 HER1 EGFR
特制应用/
erbB2 HER2 neu
erbB3 HER3
erbB4 HER4
10
EGFR stimulation cont…
TK
TK
Hetero Dimerisation
α γ β G protein
P
P
+
Ras
+
Ca++
Pyk2
Src
MAPK
Transcription
erbB Ligand Gen特e 制应用/
Steroid hormone receptor
14
How EGFR variant differs from the wild type
EGFR - Variant III
Not found in normal cells
Found normally
More propensity for cancer
Up regulation leads to cancer
特制应用/
15
35 % - 70 %
30 % - 50 %
特制应用/
6
Some Landmarks in EGFR Signalling
Stanley Cohen
❖ EGF in mice (1960’s)
❖ Human EGF (1970’s)
❖ Isolation and cloning of EGFR (1980’s). Link between EGFR and malignant transformation of cells demonstrated Mendelsohn et al.,
erbB1
erbB2
HER1
HER2
EGFRRisk for cancenr特e制u应用/
TK
erbB3 HER3
erbB4 HER4
11
EGFR Function in Normal Cell
ATP
TK
TK
ATP
+
Cell Proliferation
Gene Transcription Cell Cycle Progression
development
特制应用/
7
Human Epidermal Growth Factor Receptor Family
EGF, TGFa , b Cellulin
Amphiregulin, HB-EGF
No specific ligands often acts as dimer partner
➢ Growth Factors – The key stone ➢ A delicate balance between activating and
inhibitory signals needs to be maintained normally ➢ Alteration in this balance - Dysregulated cellular
❖ Blocking EGFR signalling to treat cancer
❖ Murine monoclonal antibodies targeting
EGFR-TK→ Human:murine chimeric version
More than 20 anti-EGFR agents in
proliferation & survival of abnormal cells.
特制应用/
3
Growth Factors & Cell Cycle
Gene Transcription
+ Receptors
S
Priming
G0
G1
Cell Cycle
G2
M
特制应用/
4
Epidermal Growth Factor Receptor (EGFR)
特制应用/
5
Tumour
Breast Colon Lung Cancer (Non small cell) Head & Neck Ovarian Pancreatic
EGFR Expression Rate
14 % - 91 %
25 % - 77 % 40 % - 80 %
80 % - 95 %
Heregulins
NRG2 NRG3 Heregulins β-cellulin
TK
erbB1 HER1 EGFR
TK
erbB2 HER2 neu特制应用/
erbB3 HER3
TK
erbB4 HER4
8
EGFR Structure
Extracellular Domain
TK
特制应用/
Transmembrane Domain Intracellular Domain
Epidermal Growth Factor Receptor (EGFR) Inhibitors
Dr.M.Jayanthi
特制应用/
1
Introduction
特制应用/
2
Cellular Signalling Pathways
➢ Vital for cell cycle progression, growth, differentiation & death.
特制应用/
Angiogenesis
Antiapoptosis
12
EGFR signal transduction in tumour cells
TK
PTEN
PI3-K pY
pY GRB2
pY
STAT3
AKT
TK
SOS
RAS RAF
MEK
Gene transcription
G1
MAPK
Proliferation/ maturation
Chemotherapy / radiotherapy resistance
M
S
G2
Angi特o制ge应n用e/sis
Survival (anti-apoptosis)
Metastasis
13
Other mechanisms of EGFR stimulation
MMP
HB-EGF
+
Steroid hormone
TK constitutively active
EGFR – Wild Type
PFra Baidu bibliotekesent Can bind TK activated by ligand binding
Cannot dimerise
Can dimerise
9
EGFR Stimulation & dimerisation
TK
TK
TK
TK
EGFR Homo Dimerisation
erbB1 HER1 EGFR
特制应用/
erbB2 HER2 neu
erbB3 HER3
erbB4 HER4
10
EGFR stimulation cont…
TK
TK
Hetero Dimerisation
α γ β G protein
P
P
+
Ras
+
Ca++
Pyk2
Src
MAPK
Transcription
erbB Ligand Gen特e 制应用/
Steroid hormone receptor
14
How EGFR variant differs from the wild type
EGFR - Variant III
Not found in normal cells
Found normally
More propensity for cancer
Up regulation leads to cancer
特制应用/
15
35 % - 70 %
30 % - 50 %
特制应用/
6
Some Landmarks in EGFR Signalling
Stanley Cohen
❖ EGF in mice (1960’s)
❖ Human EGF (1970’s)
❖ Isolation and cloning of EGFR (1980’s). Link between EGFR and malignant transformation of cells demonstrated Mendelsohn et al.,
erbB1
erbB2
HER1
HER2
EGFRRisk for cancenr特e制u应用/
TK
erbB3 HER3
erbB4 HER4
11
EGFR Function in Normal Cell
ATP
TK
TK
ATP
+
Cell Proliferation
Gene Transcription Cell Cycle Progression
development
特制应用/
7
Human Epidermal Growth Factor Receptor Family
EGF, TGFa , b Cellulin
Amphiregulin, HB-EGF
No specific ligands often acts as dimer partner
➢ Growth Factors – The key stone ➢ A delicate balance between activating and
inhibitory signals needs to be maintained normally ➢ Alteration in this balance - Dysregulated cellular
❖ Blocking EGFR signalling to treat cancer
❖ Murine monoclonal antibodies targeting
EGFR-TK→ Human:murine chimeric version
More than 20 anti-EGFR agents in
proliferation & survival of abnormal cells.
特制应用/
3
Growth Factors & Cell Cycle
Gene Transcription
+ Receptors
S
Priming
G0
G1
Cell Cycle
G2
M
特制应用/
4
Epidermal Growth Factor Receptor (EGFR)
特制应用/
5
Tumour
Breast Colon Lung Cancer (Non small cell) Head & Neck Ovarian Pancreatic
EGFR Expression Rate
14 % - 91 %
25 % - 77 % 40 % - 80 %
80 % - 95 %
Heregulins
NRG2 NRG3 Heregulins β-cellulin
TK
erbB1 HER1 EGFR
TK
erbB2 HER2 neu特制应用/
erbB3 HER3
TK
erbB4 HER4
8
EGFR Structure
Extracellular Domain
TK
特制应用/
Transmembrane Domain Intracellular Domain
Epidermal Growth Factor Receptor (EGFR) Inhibitors
Dr.M.Jayanthi
特制应用/
1
Introduction
特制应用/
2
Cellular Signalling Pathways
➢ Vital for cell cycle progression, growth, differentiation & death.
特制应用/
Angiogenesis
Antiapoptosis
12
EGFR signal transduction in tumour cells
TK
PTEN
PI3-K pY
pY GRB2
pY
STAT3
AKT
TK
SOS
RAS RAF
MEK
Gene transcription
G1
MAPK
Proliferation/ maturation
Chemotherapy / radiotherapy resistance
M
S
G2
Angi特o制ge应n用e/sis
Survival (anti-apoptosis)
Metastasis
13
Other mechanisms of EGFR stimulation
MMP
HB-EGF
+
Steroid hormone