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Introduction to the Basics of Signal Transduction. Mauricio Lema Medellín, Colombia. … Porque algunos en la audiencia no hablan español. Y ellos también fueron invitados. Signal Transduction. Introduction / Definition Components of ST Selected pathways Some newer drug targets Cross-Talk - PowerPoint PPT Presentation
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Introduction to the Basics of Signal TransductionMauricio Lema
Medellín, Colombia
… Porque algunos en la audiencia no hablan español. Y ellos también fueron invitados.
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Signal Transduction
– Introduction / Definition
– Components of ST
– Selected pathways
– Some newer drug targets
– Cross-Talk
– Concluding remarks
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Growth factors
Nutrients & O2
Hormones
Cell-Cell inter.
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Signal Transduction
Signal transduction describes the process through which extracellular signaling molecules bind specific receptors on
target cells, which consequently activate selected intracellular biochemical
pathways
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Signal Transduction - Components
– Transcription factors
– Kinases / Phosphorylases
– Adaptors
– Scafolds
– Receptors
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Signal Transduction - Components
– Transcription factors
– Kinases / Phosphorylases
– Adaptors
– Scafolds
– Receptors
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Kinases
Post-translational modifications are key to signal transduction
Phospholylation of Ser / Thr / Tyr may TURN ON / OFF a specific protein
The balance of P / de-P will establish a response
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Signal Transduction - Components
– Transcription factors
– Kinases / Phosphorylases
– Adaptors
– Scafolds
– Receptors
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Signal Transduction - Components
– Transcription factors
– Kinases / Phosphorylases
– Adaptors
– Scafolds
– Receptors
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Signal Transduction Pathways
– “Growth Factor” pathways
• Rb
• c-myc
– TGFB
– Hypoxia pathway
– mTOR
– IGR
– MET
– VEGF
– EGFR
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Anti VEGFAnti VEGF
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PI3K inhibitorsPI3K inhibitors
RAF inhibitorsRAF inhibitors
Temsirolimus /EverolimusTemsirolimus /Everolimus
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PI3K inhibitorsPI3K inhibitors
Raf InhibitorsRaf Inhibitors
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mTOR inhibitorsmTOR inhibitors
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Page 39 Proliferation MetastasisAngiogenesisApoptosis Resistance
Shc
PI3-K
RafMEKK-1
MEKMKK-7
JNKERK
Ras
mTOR
Grb2
AKT
Sos-1
Signaling EGFR
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PP
PP
ANGIOGENESIS
Survival Proliferation Migration
PLC FAKPI3-K Ras
IP3PKC AKT Paxillin MAPK
ANGIOGENESIS
Survival Proliferation Migration
PLC FAKPI3-K Ras
IP3PKC AKT Paxillin MAPK
VEGF
Binding & Activation of VEGFR
Endothelial-Cell activation
VEGF
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Let’s put it simple…
Signal – Receptor interactionSignal – Receptor interaction
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Let’s put it simple…
Signal – Receptor interactionSignal – Receptor interaction
Some P is exchangedSome P is exchanged
PI3kPI3k RasRas PKCPKC
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Let’s put it simple…
Signal – Receptor interactionSignal – Receptor interaction
Some P is exchangedSome P is exchanged
PI3kPI3k RasRas PKCPKC
Some “further” P is exchangedSome “further” P is exchanged
mTORmTOR ERKERK RbRb
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Let’s put it simple…
Signal – Receptor interactionSignal – Receptor interaction
Some P is exchangedSome P is exchanged
PI3kPI3k RasRas PKCPKC
Some “further” P is exchangedSome “further” P is exchanged
mTORmTOR ERKERK RbRb
TF – DNA interactionTF – DNA interaction EFFECTOREFFECTOR
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Signal Transduction
– Introduction / Definition
– Components of ST
– Selected pathways
– Some newer drug targets
– Cross-Talk
– Concluding remarks
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Cyclin Dependent Kinases InhibitorCyclin Dependent Kinases Inhibitor
SCH 727965 (J. Nemunaitis, P.ASCO 2009, Abstract 3535)
0/43 Responses
SCH 727965 (J. Nemunaitis, P.ASCO 2009, Abstract 3535)
0/43 Responses
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Raf Kinase InhibitorRaf Kinase Inhibitor
XL-281 (GK Schwartz, P.ASCO 2009, Abstract 3513)
1/30 PR
12/30 SD
XL-281 (GK Schwartz, P.ASCO 2009, Abstract 3513)
1/30 PR
12/30 SD
HSPHSP
Alvespimycin (SC Pacvev, P. ASCO 2009, 3534)
2/25 PR
OGX-427 (SJ Hotter, P. ASCO 2009, 3506)
5/34 SD
Alvespimycin (SC Pacvev, P. ASCO 2009, 3534)
2/25 PR
OGX-427 (SJ Hotter, P. ASCO 2009, 3506)
5/34 SD
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Akt inhibitorAkt inhibitor
MK-2206 (AW Tolcher, P.ASCO 2009, Abstract 3503)
6/19 SD
MK-2206 (AW Tolcher, P.ASCO 2009, Abstract 3503)
6/19 SD
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PI3K inhibitorsPI3K inhibitors
XL-147 (G. Shapiro, P.ASCO 2009, Abstract 3500)
6/39 SD
GDC-0941 (AJ Wagner, P.ASCO 2009, Abstract 3501)
3/19 SD
XL-765 (P. LoRusso, P.ASCO 2009, Abstract 3502)
5/34 SD
Enzastaurin (MA Carducci, P.ASCO 2009, Abstract 3517)
9/43 PR (Con Bevacizumab)
XL-147 (G. Shapiro, P.ASCO 2009, Abstract 3500)
6/39 SD
GDC-0941 (AJ Wagner, P.ASCO 2009, Abstract 3501)
3/19 SD
XL-765 (P. LoRusso, P.ASCO 2009, Abstract 3502)
5/34 SD
Enzastaurin (MA Carducci, P.ASCO 2009, Abstract 3517)
9/43 PR (Con Bevacizumab)
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IGF1R/Aurora/SRC inhibitorIGF1R/Aurora/SRC inhibitor
XL 228 (DC. Smith, P.ASCO 2009, Abstract 3512)
1/30 PR
9/30 SD
XL 228 (DC. Smith, P.ASCO 2009, Abstract 3512)
1/30 PR
9/30 SD
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MET InhibitorMET Inhibitor
ARQ 197 (TA Yap, P. ASCO 2009, Abstract 3523)
11/29 SD
PF-02341066 (EL Kwak, P. ASCO 2009, Abstract 3509)
3/10 PR NSCLC
4/10 SD NSCLC
ARQ 197 (TA Yap, P. ASCO 2009, Abstract 3523)
11/29 SD
PF-02341066 (EL Kwak, P. ASCO 2009, Abstract 3509)
3/10 PR NSCLC
4/10 SD NSCLC
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Specificity of BCR-ABL and RTK inhibitors
TK TK
ErbB1
TK TK
ErbB2
TK
TK
TK
TK
FLT3
TK
TK
TK
TK
cKIT
TK
TK
TK
TK
PDGFR
TK
TK
TK
TK
VEGFR1/2
ImatinibGleevec
NilotinibTasigna
DasatinibSprycel
ErlotinibTarceva
GefitinibIressa
LapatinibTykerb
Semaxinib SU5416
VatalanibPTK-787
SunitinibSutent
SorafenibNexavar
Bcr AblImatinib-resistant
Bcr Abl
Src
TK TK
IGF-R
OSI-PQIP
c-Raf
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Shc
PI3-K
RafMEKK-1
MEKMKK-7
JNKERK
Ras
mTOR
Grb2
AKT
Sos-1
Which Target?
Page 54 Courtesy of I. Serebriiskii and E. Golemis, Fox Chase Cancer Center.
Sos-1
Ras
MEKK-1MEK
Shc
PI3-K
Raf
MKK-7
Grb2
AKT
JNK
ERK
Page 55 Courtesy of I. Serebriiskii and E. Golemis, Fox Chase Cancer Center.
Sos-1
Ras
MEKK-1MEK
Shc
PI3-K
Raf
MKK-7
Grb2
AKT
JNK
ERK
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Concluding remarks
Understandig ST
Any significant advance in cancer care is likely to be the result of successful manipulation of STPs.
Essential for any PROLIFERATIVE condition
Dozens of potentially „druggable“ targets
The FutureIn normal cells, ST is essential for homeostasis
Growth
Differntiation
Proliferation
Complex interactions among different STPs preclude straighforward predictions of response
But...
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Back-up slides
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Specificity of BCR-ABL and RTK inhibitors
TK TK
ErbB1
TK TK
ErbB2
TK
TK
TK
TK
FLT3
TK
TK
TK
TK
cKIT
TK
TK
TK
TK
PDGFR
TK
TK
TK
TK
VEGFR1/2
ImatinibGleevec
NilotinibTasigna
DasatinibSprycel
ErlotinibTarceva
GefitinibIressa
LapatinibTykerb
Semaxinib SU5416
VatalanibPTK-787
SunitinibSutent
SorafenibNexavar
Bcr AblImatinib-resistant
Bcr Abl
Src
TK TK
IGF-R
OSI-PQIP
c-Raf
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Shc
PI3-K
RafMEKK-1
MEKMKK-7
JNKERK
Ras
mTOR
Grb2
AKT
Sos-1
Which Target?
Page 72 Courtesy of I. Serebriiskii and E. Golemis, Fox Chase Cancer Center.
Sos-1
Ras
MEKK-1MEK
Shc
PI3-K
Raf
MKK-7
Grb2
AKT
JNK
ERK
Page 73 Courtesy of I. Serebriiskii and E. Golemis, Fox Chase Cancer Center.
Sos-1
Ras
MEKK-1MEK
Shc
PI3-K
Raf
MKK-7
Grb2
AKT
JNK
ERK
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EGFREGFR
EGF
Engineer’s perspective
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