inhibidores tirosin- quinasa frente a egfr · caicun zhou , et al. erlotinib versus chemotherapy as...
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Inhibidores Tirosin-Quinasa frente a
EGFR Montse Sanchez-Cespedes
Cancer Epigenetics & Biology Program-PEBC Bellvitge Biomedical Research Institute-IDIBELL
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(Global Cancer, Facts & Figures 2011, American Cancer Society, www.cancer.org)
Primera causa de fallecimiento debida a cáncer:
o Ausencia de terapias plenamente efectivas + difícil diagnóstico
temprano
o Tasa de supervivencia a 5 años: 5-15%
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SMALL CELL LUNG CANCER (SCLC)
20% OF THE LUNG TUMORS
Highly associated with smoking habit
Non resectable
HISTOGENESIS OF LUNG CARCINOMAS
SQUAMOUS CELL CARCINOMA (SCC)
80% OF THE LUNG TUMORS
NON-SMALL CELL LUNG CANCER (NSCLC)
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Subtypes:
Acinar AC
Papillary AC
Bronchiloalveolar carcinoma (BAC)
Solid AC with mucin
AC mixed subtype
ADENOCARCINOMA (AC)
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TP53
CDKN2A
RB
KRAS
NRAS
MYCN
MYCL
MYC
Green=oncogenes
Red: Tumor suppressor genes
PTEN
YEAR 2000
YEAR 2000
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TP53
CDKN2A
LKB1 BRG1
PTEN
RB
APC
SMAD4
NRAS
PIK3CA
ERBB2
EGFR
BRAF
CMET
MYCN
MYCL
MYC
ALK
NF1
NF2
CTNNB1
ATM
Green:Oncogenes
Red:Tumor suppressor genes
Grey: to be confirmed
YEAR 2012
KRAS
PIK3R1
PARD3
EPHA3
LRP1B
PTPRD
NTRK3
KIT/
PDGFRA
RET
ROS
KEAP1
PARD3B
ARID1A
ARID2
FGFR1
RBM10
U2AF1
MLL2
MLL4
MLL3
CREBBP
SLIT2
DDR2
EPHA7
EP300
MAX
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RB MAX CREBBP EP300
EGFR, ERBB2 ALK,ROS,RET KRAS,NRAS
LKB1
TP53 MYC
CDKN2A BRG1
PIK3CA
PTEN
SCLC
SCC
AC
Others*
-ATM
-BRAF
-CMET
-CTNNB1
-NF1/2
-SMAD4
Actualizado de Sanchez-Cespedes. Clin Tras Oncol.2009
PARD3
FGFR1
DDR2
KEAP1
GENES ALTERADOS EN CANCER DE PULMON
SEGUN LA HISTOPATOLOGIA
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ACTUALIZACION DE LA GENETICA /BIOLOGIA DEL EGFR EN EL CÁNCER DE PULMÓN
ALTERACIONES GENETICAS DE EGFR COMO MARCADOR PREDICTIVO DE RESPUESTA A INHIBIDORES DE TIROSINA QUINASA (RESISTENCIA INTRINSECA O PRIMARIA)
FACTORES DETERMINANTES DE LA RESISTENCIA SECUNDARIA O ADQUIRIDA A INHIBIDORES DE EGFR.
OTROS RECEPTORES CON ACTIVIDAD TIROSINA QUINASA COMO DIANAS TERAPEUTICAS EN EL CÁNCER DE PULMON
PUNTOS A TRATAR:
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ACTUALIZACION DE LA GENETICA /BIOLOGIA DEL EGFR EN EL CÁNCER DE PULMÓN
ALTERACIONES GENETICAS DE EGFR COMO MARCADOR PREDICTIVO DE RESPUESTA A INHIBIDORES DE TIROSINA QUINASA (RESISTENCIA INTRINSECA O PRIMARIA)
FACTORES DETERMINANTES DE LA RESISTENCIA SECUNDARIA O ADQUIRIDA A INHIBIDORES DE EGFR.
OTROS RECEPTORES CON ACTIVIDAD TIROSINA QUINASA COMO DIANAS TERAPEUTICAS EN EL CÁNCER DE PULMON
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EPIDERMAL GROWTH FACTOR RECEPTOR
(EGFR) INDEPENDENCE OF MITOGENIC STIMULI
Adapted from Vogelstein and Kinzler, Nat Med, 2004
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EPIDERMAL GROWTH FACTOR RECEPTOR (EGFR) MUTATIONS IN NSCLC
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Pao, W. et al. J Clin Oncol; 23:2556-2568 2005
PROFILE OF EGFR MUTACIONS IN LUNG CANCER
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Exon Change
19 2235-2249del GGAATTAAGAGAAGC E746-A750del 4/86
19 2237-2251del AATTAAGAGAAGCAA E746-A750del 1/86
19 2240-2251del TAAGAGAAGCAA L747-T751del 1/86
19 2239-2247del TTAAGAGAA, 2248G>C L747-E749del, A750P 1/86
21 2573T>G L858R 4/86
Total 11/86 (13%)
Effect Frequency
Conde et al. Clin Cancer Res, 2006
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ACTUALIZACION DE LA GENETICA /BIOLOGIA DEL EGFR EN EL CÁNCER DE PULMÓN
ALTERACIONES GENETICAS DE EGFR COMO MARCADOR PREDICTIVO DE RESPUESTA A INHIBIDORES DE TIROSINA QUINASA (RESISTENCIA INTRINSECA O PRIMARIA)
FACTORES DETERMINANTES DE LA RESISTENCIA SECUNDARIA O ADQUIRIDA A INHIBIDORES DE EGFR.
OTROS RECEPTORES CON ACTIVIDAD TIROSINA QUINASA COMO DIANAS TERAPEUTICAS EN EL CÁNCER DE PULMON
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CÁNCER DE PULMON:RESPUESTA A ERLOTINIB
Erlotinib
Gazdar, Oncogene 2009
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Caicun Zhou , et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR
mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label,
randomised, phase 3 study The Lancet Oncology Volume 12, 735 – 742, 2011 .
Rafael Rosell , et al. Erlotinib versus standard chemotherapy as first-line treatment for European
patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre,
open-label, randomised phase 3 trial. The Lancet Oncology 13, 239 – 246, 2012.
RESPUESTA A ERLOTINIB: CANCER DE
PULMON CON MUTACIONES EN EGFR
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Niederst et al. Sci Sig 2013
RESISTENCIA INTRINSECA O PRIMARIA A
TKIs (TYROSINE KINASE INHIBITORS) DE EGFR
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EL CASO DE LA MUTACION T790M
Ma et al. J Thorac Dis. 2011; 3: 10–18.
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ADENOCARCINOMAS DE PULMON
NO FUMADORES O BAC/PAPILAR
FUMADORES O TUMORES NO BAC-NO PP
MUTACIONES
EN EGFR NO MUTACIONES
EN EGFR
ACTIVACION OTROS
RECEPTORES/VIAS
NO MUTACION T790M U OTROS
RECEPTORES MUTACION
T790M
ERLOTINIB COMBINATORIO:
ERLOTINIB +
OTROS
OTROS
INHIBIDORES
EGFR
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ACTUALIZACION DE LA GENETICA /BIOLOGIA DEL EGFR EN EL CÁNCER DE PULMÓN
ALTERACIONES GENETICAS DE EGFR COMO MARCADOR PREDICTIVO DE RESPUESTA A INHIBIDORES DE TIROSINA QUINASA (RESISTENCIA INTRINSECA O PRIMARIA)
FACTORES DETERMINANTES DE LA RESISTENCIA SECUNDARIA O ADQUIRIDA A INHIBIDORES DE EGFR.
OTROS RECEPTORES CON ACTIVIDAD TIROSINA QUINASA COMO DIANAS TERAPEUTICAS EN EL CÁNCER DE PULMON
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ACQUIRED RESISTANCE
MUTATIONS
CML, chronic myelogenous leukemia
HES, hypereosinophilic syndrome
GIST, gastrointestinal stromal tumor
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EGFR RESISTANT MUTATIONS:
THE CASE OF THE T790M 2005
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EGFR RESISTANT MUTATIONS: THE CASE OF MET
AMPLIFICATION
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DISTINTOS MECANISMOS RESPONSABLES DE
LA RESISTENCIA ADQUIRIDA A ERLOTINIB
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AFATINIB, UN INHIBIDIBOR IRREVERSIBLE
DE EGFR
Progression-free survival for afatinib
in patients with and without T790.
Jong-Mu Sun , et al. Lung Cancer 2013
Of the two patients with T790M
mutations in the originas tumor:
one patient harboring an
L858R + T790M mutation had
durable SD for 9 months,
and the other patient with a
del19 + T790M mutation
had SD for 1 month.
Waterfall plot of percent change from baseline in
measurable tumor at the time of best response Katakami N et al.
JCO 2013;31:3335-3341
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COMBINED TREATMENTS: MET INHIBIDIBORS
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ACTUALIZACION DE LA GENETICA /BIOLOGIA DEL EGFR EN EL CÁNCER DE PULMÓN
ALTERACIONES GENETICAS DE EGFR COMO MARCADOR PREDICTIVO DE RESPUESTA A INHIBIDORES DE TIROSINA QUINASA (RESISTENCIA INTRINSECA O PRIMARIA)
FACTORES DETERMINANTES DE LA RESISTENCIA SECUNDARIA O ADQUIRIDA A INHIBIDORES DE EGFR.
OTROS RECEPTORES CON ACTIVIDAD TIROSINA QUINASA, COMO DIANAS TERAPEUTICAS EN EL CÁNCER DE PULMON
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GFR PATHWAYS ARE ALTERED IN CANCER
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DETERMINATION OF ONCOGENIC
ACTIVATION OF GROWTH FACTOR
RECEPTORS IN LUNG CANCER
-300 lung tumors (NSCLC) disposed in tissue microarrays
(TMAs)
-Gene copy No (FISH)
ERBB2, MET, KIT/PDGFRA, FGFR1, FGFR2, FGFR3, IGF1R, ALK
-IHC or qPCRs
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MET PDGFRA KIT FGFR1
Norm
al copy N
o.
Gene a
mplif
ication
Only four regions (MET, KIT/PDGFRA, FGFR1, ERBB2) of the GFR
carried gene amplification
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NC, normal copy for <4 copies; MI, minimally increased for 4-6 copies; HI, highly increased, for 7-12 copies; GA, gene amplification for >12 copies.
Pros et al. Int J cancer, 2013
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FGFR3 KIT MET IGF1R FGFR1
Immunostaining of the GFRs
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Num
ber
of
sam
ple
s
FGFR1
NC MI HI GA0
10
20
30
40150
200
250
300
350
*** (N versus S) KIT MET IGF1R
*** (N versus S)
*** (N versus M)
* (N versus S) * (N versus S)
NC MI0
50
100
150
200
250
NC MI HI GA0
5
10
15
20100
150
200
250
NC MI GA0
5
10
15
20100
150
200
250 S
M/W
N
NC MI HI GA0
2
4
6
8
10
NC MI HI GA0
2
4
6
8
10
FG
FR
1 le
vels
of
expre
ssio
n
rela
tive to I
PO
8
** *
NC MI HI GA0.0
0.5
1.0
12.0
NC MI HI GA0.0
0.5
1.0
12.0
PD
GF
RA
le
vels
of
expre
ssio
n
rela
tive to I
PO
8
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CONCLUSIONS
LUNG CANCER HAVE MUTATIONS / ALTERATIONS IN MULTIPLE ONCOGENES AND TUMOR SUPPRESSOR GENES WHICH IS THE GENETIC PROFILE OF EACH TUMOR.
THE GENETIC PROFILE OF EACH LUNG TUMOR IS CLOSELY RELATED TO THE HISTOPATHOLOGIC TYPE.
EGFR MUTATIONS ARE RELATIVELY COMMON IN NONSMOKERS PATIENTS WITH ADENOCARCINOMAS. THESE MUTATIONS CONFER SENTITIVITY TO TYROSINE KINASE INHBITORS.
SENSITIVITY/RESISTANCE INTRINSIC (PRIMARY): THE PRESENCE OF THE EGFR MUTATION IS NECESSARY BUT NOT SUFFICIENT. ALTERATIONS IN OTHER TK RECEPTORS ACTING IN PARALEL SIGNALLING MAY CONFER RESISTANCE.
ACQUIRED RESISTANCE (SECONDARY): ACQUIRED RESISTANCE TO A GIVEN DRUG. EITHER GENETIC CHANGES IN THE MOLECULE THAT IS THE TARGET OF THE DRUG: T790M, OR ALTERATIONS IN OTHER TK RECEPTORS ACTING IN PARALEL SIGNALLING.
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Collaborators
Centro Nacional de Investigaciones Oncológicas (Madrid) Immunohistochemistry Unit: Lydia Sanchez-Verde Cytogenetics Unit: Juan C Cigudosa Centro de Investigaciones Médicas Aplicadas (Pamplona) Luis Montuenga Ruben Pio Centro Integral Oncológico Clara Campal (Madrid) Fernando Lopez-Rios Ana Suarez-Gauthier Esther Conde Vall d’Hebron (Barcelona) Santiago Ramon y Cajal Josep Castellvi National Cancer Center Research Institute (Tokyo, Japan) Jun Yokota Takashi Kohno Département d'Anatomie et Cytologie Pathologiques (Grenoble, France) Elisabeth Brambilla Fondazione IRCCS - Istituto Nazionale Tumori (Milano, Italy) Dr. Luca Roz
Genes and Cancer Group-IDIBELL Octavio A. Romero Ester Bonastre Manuel Torres-Diz Carolina Pereira Eva Pros Patricia Cabral Rossana Gonçalves