la via pi3k/akt - seom
TRANSCRIPT
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La via PI3K/AKTO
ON
N
NOH
N
O
N
N
NHS
O
OO
O
O
N
O
O
O
H OH
N
N
O
OH
N
NN
N
N
NH
O
SNH
NO
AMANCIO CARNEROIBIS/CSIC, Sevilla
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La via PI3K/AKT
PTEN
Ciclo celularApoptosis
Ciclo celularMetabolismo
CrecimientoTraslacion
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La via PI3K/AKT en Cancer
PI3K Cancer de mama
GFRec.
PI3KMutaciones activantes,
Amplificacion y derregulacion. (Roymans and Slegers, 2001)
Carcinoma de ovarioAdenocarcinoma de pulmonCancer colorectal
PI3´KPIP2
Ras
AKTPIP3 PDK1PTEN
APOPTOSISRasMutado en muchos
tipos tumorales
AKTFrequently amplified
i lid t
tipos tumoralesin many cancers(el-Deiry, 1997) PTEN
Mutado o metilado en
Mutacion germinal en -Cowden (tumores malignos)-Lhermitte-Duclos, Bannayan-Zoana, Proteus in solid tumors
Mutaciones activantesinfrecuentes
(Datta et al., 1999)
muchos tipostumoralesEspecialmente metastasis
(Di Cristofano and Pandolfi, 2000) Mutaciones/metilaciones
i t d l ti
y ,syndromes (harmatomas Y tumores benignos)
, )en casi todos los tipos tumorales
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Activacion de la via PI3K/AKT en Cancer:Un ejemplo en prostata
Normal Tissue AdenoCa
Un ejemplo en prostata
AKT-P
eIF4G-P
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Familia PI3K
C t l ti b it R l t b it
p110α, p110β, p110δp110γ
p85, p55, p50p101
Catalytic subunit Regulatory subunit
Class IA:IB
PI3KC2α, PI3KC2β, PI3KC2γClass II:
VsP34Class III:
mTor ATM ATR DNA-PKClass IV: mTor, ATM, ATR, DNA-PKClass IV:
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Fosfatidilinositol, 3 kinasa: PI3K
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Mutaciones en PI3K son oncogenicas
E542K
E545K H1047R
p85bd RasBD KinaseHelicalC2
8% 47% 33%
Mutante Oncogenicidad
E542K, E545K, H1047R ++++
N345K, C420R, H147L, P539R,E545G, Q546K
+++
E545A T1025S M1043I ++E545A, T1025S, M1043I, M1043V, H1047Y
++
R38H, K11N +
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PI3K como diana terapeutica
Zhao et al, PNAS 2007
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PI3KCAH1047R Condicional Transgen: una validacion elegante
PI3KCA(1047H)CCSP (lung)
control BEZ235
9 months + doxi
K G12D9 months + doxi3 weeks w/o
ors
KrasG12D
Conditional KI mouse
% t
umo
Engelman et al. Nat. Med. (2008)
C Bez Arry Bez+Arry
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Interaccion Ras-PI3K
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Fosfatasa de lipidos PTEN
PTEN
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Modelo PTEN knock-out
KO mice L t lid d b i i
Hiperplasia en prostata piel y
KO mice Linea germinal Letalidad embrionaria
Hiperplasia en prostata, piel y colon, llegando a producir tumores en tiroides, colon y otros tejidos Reproduce fenotipo
Linea germinalheterozigosis
tejidos. Reproduce fenotipo sindromes humanos (cowden…)
Condicional KO miceTejido especifico
Aumento hiperplasia y propiedades tumorales llegando a dar tumores en la mayor parte de t jid t t dtejidos testados
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Perdida de PTEN produce tumores
Perdida de PTEN en mama produce Adenocarcinoma
●Li, G. et al. Development 2002;129:4159-4170
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AKT “master kinase”
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AKT es necesaria para supervivencia
Con p110α p110β p110δ p110γ
10%FBS
A3
- FBS
p
cDN
A
10%FBS
9M
- FBS
AKTK
179
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Circuito retroalimentado por mTOR: una dualidad peligrosau a dua dad pe g osa
RTK GPCR
PIPPIP
IRS-1
PIP3PI3Kα,β,δ
PTEN
PI3Kγ
PIP3PIP3PIP3PIP3PIP3
PIP3
PI3Kα,β,δ
PIP2
PTEN
T308 S473DNAPK
TSC1/2
mTORC1 mTORC2
mTOR Raptor mTOR Rictor
S6K 4E-BPs
mRNA translation
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mTORC1
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Regulacion de la localizacion de FOXO por PI3Kpor PI3K
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Importancia de la localizacion l d FOXOnuclear de FOXO
control 3.5 hrs LY
P EN control
PTEN mutPI3K activado
No PI3Kactivacion
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Foxo factor de transcripcionDifferentiationDifferentiation
BTG-1p21 Glucose Metabolism
G6Pase
PEPCK
ROS catalaseG1 Arrest
p27
p21
ROS Detoxification
MnSOD
G2 DelayCyclin G2
Target genesDBE
FOXO
Muscle AtrofyGADD45
GADD45
Muscle Atrofy
Atrogin-1DNA Repair
DDB1
G 5
Cell DeathFasL
BIM
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Efectos de FOXO
TransformacionProliferacion autonoma
EvaA
po asion de optosisParace de ciclo e
induccion de apoptosisp21KIP1 BIM FasL
Proteccion a daño Aumento apoptosis:BIM, FasL, BNIP3L
p21 , BIM, FasL
oxidativo y al ADN:MnSOD, Catalasa, GADD45
AngiogennesisBloqueo HIF:
MnSOD, Catalasa
FOXO
Invasion or Metastasis
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La via PI3K/AKT como diana terapeutica
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Mutaciones en la via PI3K no son l texcluyentes
Mutaciones
PTEN-, PI3Kmut
Mama
Coexisten
Endometrio
Coexisten
Colon
CoexistenPTEN , PI3K
Ras mut, PI3Kmut
Coexisten
AparenteExcluyentes
Coexisten
Excluyentes
Coexisten
Coexisten
Ras mut, PTEN-
Her2+, PI3Kmut
yAparente ExcluyentesCoexisten
Coexisten
NA
Coexisten
NA
Her2+, PTEN- Coexisten NA NA
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PTEN, algo mas que la via PI3K
TextoPIP2 PIP3 PIP3 PIP3
Akt
PDK1p110
85P P pleckstrin homology (PH)
F b1 YOTB V 27
PTEN
p85
PI3KinaseMaster kinase
Fab1p, YOTB, Vps27p, EEA1 (FYVE), (ENTH))Phox homology (PX),
Akt
ras
AGC kinase familyAkt
Active
AGC kinase familySGKs, PKA S6K, RSK PKC βΙΙ δ ζ
P53pCAF p300 PKCα, βΙΙ, δ, ζ
protein kinase NpCAF, p300Ra51 pomoterMAPKCyclin D1Cyclin D1
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Tumor supresors y oncogenes en la via de PI3K
ErbB2, IGF-1R, EGFR PDGFRRTKsAdaptorEGFR, PDGFR,…
p85p110 Ras
PIP2
PTENp53
Migracion
pPIP3
MDM2
IKKNFkB AKT PDK1 RacIKKNFkB
Bad14-3-3
FOXO TSC1TSC2GSK3
Bim Rh b
SGK LKB1
Cyclin D1p27kip1 MycBcl-XL
BimFasL
Rb2S6
S6KmTOR
4E BP1
Rheb
Supervivencia Ciclo celular Sintesis ProteinasCrecimiento celular
S64E-BP1
Crecimiento celular
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Conclusiones
L i d PI3K/AKT l t d l l l La via de PI3K/AKT regula gran parte de los procesos celulares esenciales para la supervivencia celular
Esta altamente alterada en cancerEsta altamente alterada en cancer
Esta siendo utilizada en el desarrollo de nuevas terapias para generar farmacos dirigidos a dianas concretasgenerar farmacos dirigidos a dianas concretas
Aun hay ciertos aspectos que conviene investigar para personalizar la terapia dirigida a esta viapersonalizar la terapia dirigida a esta via
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Inhibidores PI3KO
OO
ON NH2 O
H
ON
O
O
N
O
O
O
H OH
O
O
O
O
O
H
O
O
ON
O
H
N
NH
O
N NH
O
O
OH
OOHH
OHH
(1) LY294002O
OH OH
(4) PX-866O
H
(3) WortmanninO N
O(2) SF1126+
O N
N
O
NS
N
O
NN
N
Me O
MeN
N
OH
NH2
(8) GDC-0941 (7) PI-103
ON
N
NOH N
NN NH
SO
O
NN
N
N
N
NH2
(5) IC87114N N
OH
NH2
(6) TG100115
N
O
N
2
N
N
N
N
ON N
N
FF
NN
N
N
O
SNH
NO
ON
N
NHS
O
O
(9) ZSTK474(10) BEZ235
N(11) GSK1059615
O(12) AS605240
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Efecto Inhibidores de PI3K
Akt-P (Ser473)
Akt-P (Thr308)
Akt
p70S6-P (Thr398)
Foxo P (Thr32)Foxo-P (Thr32)
GSK3-β-P (Ser9)
Foxo
P44/P42 MAPK (Erk-P)
CyclinD1
α-tubulin
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Expression of myr.p110 Expression of myr.p110 p y pprotects against Akt1 dephosphorylation that occurs in the absence of
p y pprotects from c-myc induced apoptosis in the absence of serum
serum
+p110αRcM 90
100
90
100
ity
m+p110αRcM + – + –FBS
50
60
70
80
50
60
70
80
pase
act
iv1%
ser
u m
AKT-P
10
20
30
40
10
20
30
40
% C
asp
at 0
.
0
10
RcM0
10
+p110α
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UV and survival of prostate cell lines in presence or absence of PI3Ki
val
120
140
cell lines in presence or absence of PI3Ki.el
l sur
viv
60
80
100 PC-3
DU-145
% C
e
20
40
60
0
10 J/m2 30 J/m2 50 J/m2
rviv
al60
80
% s
u
20
40Akt- P Ser473
0
50 µM LY0
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La via PI3K/AKT
RTK GPCR
IRS-1
PIP3PI3Kα,β,δ
PTEN
PIP3 PI3Kγ
PIP3PIP3
PIP2PI3Kα,β,δ
TSC1/2
FoxoBad GSK3
nutrient response cell survival cell-cyclemetabolism
Rac
migration
mTOR
nutrient responsecell and organ sizecell-cycleprotein translation
cell survival cell cyclecell survivalmetabolismDNA damage
metabolismcell-cycle
migration