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Estructura del receptor esteroideo · Mecanismos de Resistencia Hormonal en Cáncer de Mama In the majority of primary breast cancers, the ER-negative phenotype is not the result

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Page 1: Estructura del receptor esteroideo · Mecanismos de Resistencia Hormonal en Cáncer de Mama In the majority of primary breast cancers, the ER-negative phenotype is not the result
Page 2: Estructura del receptor esteroideo · Mecanismos de Resistencia Hormonal en Cáncer de Mama In the majority of primary breast cancers, the ER-negative phenotype is not the result

Receptores Esteroideos

R. intracelulares, que actuan como factores de transcripcion regulando laexpresión de genética

Son Receptores Esteroideos:Receptor Glucocorticides

Receptor MineralocorticoidesReceptor a ProgesteronaReceptor a AndrogenosReceptor a EstrogenosReceptor Hormona TiroideaReceptor para Vitamina DReceptor para Acido Retinoico

Mecanismos de Resistencia Hormonalen Cáncer de Mama

Page 3: Estructura del receptor esteroideo · Mecanismos de Resistencia Hormonal en Cáncer de Mama In the majority of primary breast cancers, the ER-negative phenotype is not the result

Estructura del receptor esteroideo

Tres regiones bien conservadas

• Dominio de Union a Hormona (DBH)

• Dominio de Union a DNA (DBD)

• Region Hipervariable. Modulador de la actividad transcripcional del receptor

Mecanismos de Resistencia Hormonalen Cáncer de Mama

Page 4: Estructura del receptor esteroideo · Mecanismos de Resistencia Hormonal en Cáncer de Mama In the majority of primary breast cancers, the ER-negative phenotype is not the result

RE

Dimerizacióndel receptor

Adaptado de: Wakeling AE. Endocr-Relat Cancer 2000; 7: 17–28.

EREARN

POL II

TRANSCRIPCIÓNCOMPLETAMENTEACTIVADA (división de lacélula tumoral)

FA2

EE

FA1

Coactivador

Coactivador

Mecanismo de Acción Genómico Clásico

Mecanismos de Resistencia Hormonalen Cáncer de Mama

Page 5: Estructura del receptor esteroideo · Mecanismos de Resistencia Hormonal en Cáncer de Mama In the majority of primary breast cancers, the ER-negative phenotype is not the result

Mecanismos de Resistencia Hormonalen Cáncer de Mama

RE

Adaptado de: Wakeling AE. Endocr-Relat Cancer 2000; 7: 17–28.

EREARN

POL II

TRANSCRIPCIÓNCOMPLETAMENTEACTIVADA (división de lacélula tumoral)

Mecanismo de Acción Genómico no-Clásico

Page 6: Estructura del receptor esteroideo · Mecanismos de Resistencia Hormonal en Cáncer de Mama In the majority of primary breast cancers, the ER-negative phenotype is not the result

Mecanismos de Resistencia Hormonalen Cáncer de Mama

RE

Adaptado de: Wakeling AE. Endocr-Relat Cancer 2000; 7: 17–28.

EREARN

POL II

TRANSCRIPCIÓNCOMPLETAMENTEACTIVADA (división de lacélula tumoral)

Mecanismo de Acción no-Genómico

Page 7: Estructura del receptor esteroideo · Mecanismos de Resistencia Hormonal en Cáncer de Mama In the majority of primary breast cancers, the ER-negative phenotype is not the result

TumorMicroenvironment

NR:ER: variants,

loss

ERβEERAR

Coregulators

TKR/GF:EGFR/HER2IGFR, FGFR, VEGFR2FGFR

Cellular Kinases:MEK/MAPK

PTEN/PI3K/AktP38/JNKSRC/FAK

TF:AP1SP1NFkB

StressResponses:TreatmentsCytokines

HypoxiaOS/ROS

F

T

AI

F AI

T+ Integrins

E2FPathways:

Cell Cycle (Cyclin D, E) Survival (Bcl, BAD) Proliferation (Myc)

REPRODUCED FROM: Osborne CK & Schiff R.. Ann Rev Med 2011 & Sparano ASCO 2015 and Ignatiadis et al. Nat Rev Clin Oncol 2013

Mecanismos de resistencia

Classical

genomic

Non-classical

genomic

Page 8: Estructura del receptor esteroideo · Mecanismos de Resistencia Hormonal en Cáncer de Mama In the majority of primary breast cancers, the ER-negative phenotype is not the result

Mecanismos de Resistencia Hormonalen Cáncer de Mama

Hormo-RESISTENCIA

Page 9: Estructura del receptor esteroideo · Mecanismos de Resistencia Hormonal en Cáncer de Mama In the majority of primary breast cancers, the ER-negative phenotype is not the result

Mecanismos de Resistencia Hormonalen Cáncer de Mama

Concepto Clínico:Progresión de la enfermedad durante un tratamiento o al poco tiempo de su finalización.

Page 10: Estructura del receptor esteroideo · Mecanismos de Resistencia Hormonal en Cáncer de Mama In the majority of primary breast cancers, the ER-negative phenotype is not the result

Mecanismos de Resistencia Hormonalen Cáncer de Mama

Concepto Clínico:Progresión de la enfermedad durante un tratamiento o al poco tiempo de su finalización.

Resistencia Natural: Ausencia de actividad desde el principio.

Resistencia Adquirida: Durante una exposición crónica y eficaz se desarrollan mecanismos celulares de protección y el tumor crece.

Resistencia Intrínseca: Tras exposición eficaz y (limitada en el tiempo) crecen los clones resistentes al tratamiento.

Page 11: Estructura del receptor esteroideo · Mecanismos de Resistencia Hormonal en Cáncer de Mama In the majority of primary breast cancers, the ER-negative phenotype is not the result

Mecanismos de Resistencia Hormonalen Cáncer de Mama

Concepto Clínico:Progresión de la enfermedad durante un tratamiento o al poco tiempo de su finalización.

Page 12: Estructura del receptor esteroideo · Mecanismos de Resistencia Hormonal en Cáncer de Mama In the majority of primary breast cancers, the ER-negative phenotype is not the result

Mecanismos de Resistencia Hormonalen Cáncer de Mama

En cáncer de de mama …

1.-Un 30-40 % de la pacientes son resistentes a Tratamiento Hormonal

2.- El 100% de la las pacientes se hacen resistentes a Tratamiento Hormonal

Page 13: Estructura del receptor esteroideo · Mecanismos de Resistencia Hormonal en Cáncer de Mama In the majority of primary breast cancers, the ER-negative phenotype is not the result

Mecanismos de Resistencia Hormonalen Cáncer de Mama

En cáncer de de mama …

1.-Un 50% de la pacientes son resistentes a Tratamiento Hormonal

2.- El 100% de la las pacientes se hacen resistentes a Tratamiento Hormonal

Page 14: Estructura del receptor esteroideo · Mecanismos de Resistencia Hormonal en Cáncer de Mama In the majority of primary breast cancers, the ER-negative phenotype is not the result

Mecanismos de Resistencia Hormonalen Cáncer de Mama

EL RECEPTOR NO SE EXPRESA

Page 15: Estructura del receptor esteroideo · Mecanismos de Resistencia Hormonal en Cáncer de Mama In the majority of primary breast cancers, the ER-negative phenotype is not the result

Mecanismos de Resistencia Hormonalen Cáncer de Mama

In the majority of primary breast cancers, the ER-negative phenotype is not the result of mutations in the coding region of the ER gene, but is due to deficient ER expression at the transcriptional or post-transcriptional level

Estrogen Receptor Gene Analysis in Estrogen Receptor-Positive and Receptor-Negative Primary Breast Cancer

Nady Roodi, L. Renee Bailey, Woei-Yau Kao, Carmel S. Verrier, Cindy J. Yee, William D. Dupont, Fritz F. Parl

Son

http://jnci.oxfordjournals.org/current.dtl
Page 16: Estructura del receptor esteroideo · Mecanismos de Resistencia Hormonal en Cáncer de Mama In the majority of primary breast cancers, the ER-negative phenotype is not the result

Mecanismos de Resistencia Hormonalen Cáncer de Mama

In the majority of primary breast cancers, the ER-negative phenotype is not the result of mutations in the coding region of the ER gene, but is due to deficient ER expression at the transcriptional or post-transcriptional level

Estrogen Receptor Gene Analysis in Estrogen Receptor-Positive and Receptor-Negative Primary Breast Cancer

Nady Roodi, L. Renee Bailey, Woei-Yau Kao, Carmel S. Verrier, Cindy J. Yee, William D. Dupont, Fritz F. Parl

Son

http://jnci.oxfordjournals.org/current.dtl
Page 17: Estructura del receptor esteroideo · Mecanismos de Resistencia Hormonal en Cáncer de Mama In the majority of primary breast cancers, the ER-negative phenotype is not the result

Mecanismos de Resistencia Hormonalen Cáncer de Mama

In the majority of primary breast cancers, the ER-negative phenotype is not the result of mutations in the coding region of the ER gene, but is due to deficient ER expression at the transcriptional or post-transcriptional level

Estrogen Receptor Gene Analysis in Estrogen Receptor-Positive and Receptor-Negative Primary Breast Cancer

Nady Roodi, L. Renee Bailey, Woei-Yau Kao, Carmel S. Verrier, Cindy J. Yee, William D. Dupont, Fritz F. Parl

Son

http://jnci.oxfordjournals.org/current.dtl
Page 18: Estructura del receptor esteroideo · Mecanismos de Resistencia Hormonal en Cáncer de Mama In the majority of primary breast cancers, the ER-negative phenotype is not the result

Mecanismos de Resistencia Hormonalen Cáncer de Mama

EL RECEPTOR ESTA

CO-MODULADO

Page 19: Estructura del receptor esteroideo · Mecanismos de Resistencia Hormonal en Cáncer de Mama In the majority of primary breast cancers, the ER-negative phenotype is not the result

Mecanismos de Resistencia Hormonalen Cáncer de Mama

Son

Page 20: Estructura del receptor esteroideo · Mecanismos de Resistencia Hormonal en Cáncer de Mama In the majority of primary breast cancers, the ER-negative phenotype is not the result

Mecanismos de Resistencia Hormonalen Cáncer de Mama

EL RECEPTOR TIENE MENOR AFINIDAD POR EL INHIBIDOR

Page 21: Estructura del receptor esteroideo · Mecanismos de Resistencia Hormonal en Cáncer de Mama In the majority of primary breast cancers, the ER-negative phenotype is not the result

Mecanismos de Resistencia Hormonalen Cáncer de Mama

Son

Page 22: Estructura del receptor esteroideo · Mecanismos de Resistencia Hormonal en Cáncer de Mama In the majority of primary breast cancers, the ER-negative phenotype is not the result

Mecanismos de Resistencia Hormonalen Cáncer de Mama

Son

Page 23: Estructura del receptor esteroideo · Mecanismos de Resistencia Hormonal en Cáncer de Mama In the majority of primary breast cancers, the ER-negative phenotype is not the result

Mecanismos de Resistencia Hormonalen Cáncer de Mama

Son

Page 24: Estructura del receptor esteroideo · Mecanismos de Resistencia Hormonal en Cáncer de Mama In the majority of primary breast cancers, the ER-negative phenotype is not the result

Mecanismos de Resistencia Hormonalen Cáncer de Mama

MODIFACIONES EN LA METABOLIZACIÓN DEL FARMACO

Page 25: Estructura del receptor esteroideo · Mecanismos de Resistencia Hormonal en Cáncer de Mama In the majority of primary breast cancers, the ER-negative phenotype is not the result

Mecanismos de Resistencia Hormonalen Cáncer de Mama

Son

Page 26: Estructura del receptor esteroideo · Mecanismos de Resistencia Hormonal en Cáncer de Mama In the majority of primary breast cancers, the ER-negative phenotype is not the result

Mecanismos de Resistencia Hormonalen Cáncer de Mama

Son

Page 27: Estructura del receptor esteroideo · Mecanismos de Resistencia Hormonal en Cáncer de Mama In the majority of primary breast cancers, the ER-negative phenotype is not the result

Mecanismos de Resistencia Hormonalen Cáncer de Mama

Son

Page 28: Estructura del receptor esteroideo · Mecanismos de Resistencia Hormonal en Cáncer de Mama In the majority of primary breast cancers, the ER-negative phenotype is not the result

Mecanismos de Resistencia Hormonalen Cáncer de Mama

PERFIL DE

RESISTENCIA

Page 29: Estructura del receptor esteroideo · Mecanismos de Resistencia Hormonal en Cáncer de Mama In the majority of primary breast cancers, the ER-negative phenotype is not the result

Mecanismos de Resistencia Hormonalen Cáncer de Mama

Son

Page 30: Estructura del receptor esteroideo · Mecanismos de Resistencia Hormonal en Cáncer de Mama In the majority of primary breast cancers, the ER-negative phenotype is not the result

Mecanismos de Resistencia Hormonalen Cáncer de Mama

Extended TTP in Patients Predicted to Respond to Tamoxifen

Kok M, et al. SABCS 2006. Abstract 47.

81-genes: nonresponder

81-genes: responder

No. of At-Risk Patients

TTP (Months)

Median TTP 7 vs 21 monthsP = .002 (log rank)

Tum

or

Pro

gre

ssio

n (

%)

100

0

80

60

40

20

06 12 18 24 30 36

32 29 25 17 12 7 537 22 13 8 5 3 2

Son

Page 31: Estructura del receptor esteroideo · Mecanismos de Resistencia Hormonal en Cáncer de Mama In the majority of primary breast cancers, the ER-negative phenotype is not the result

Mecanismos de Resistencia Hormonalen Cáncer de Mama

En cáncer de de mama …

1.-Un 50% de la pacientes son resistentes a Tratamiento Hormonal

2.- El 100% de la las pacientes se hacen resistentes a Tratamiento Hormonal

Page 32: Estructura del receptor esteroideo · Mecanismos de Resistencia Hormonal en Cáncer de Mama In the majority of primary breast cancers, the ER-negative phenotype is not the result

Mecanismos de Resistencia Hormonalen Cáncer de Mama

Se hacen

Page 33: Estructura del receptor esteroideo · Mecanismos de Resistencia Hormonal en Cáncer de Mama In the majority of primary breast cancers, the ER-negative phenotype is not the result

Mecanismos de Resistencia Hormonalen Cáncer de Mama

Se hacen

LTED

Page 34: Estructura del receptor esteroideo · Mecanismos de Resistencia Hormonal en Cáncer de Mama In the majority of primary breast cancers, the ER-negative phenotype is not the result

Mecanismos de Resistencia Hormonalen Cáncer de Mama

Se hacen

Page 35: Estructura del receptor esteroideo · Mecanismos de Resistencia Hormonal en Cáncer de Mama In the majority of primary breast cancers, the ER-negative phenotype is not the result

Mecanismos de Resistencia Hormonalen Cáncer de Mama

Se hacen

Page 36: Estructura del receptor esteroideo · Mecanismos de Resistencia Hormonal en Cáncer de Mama In the majority of primary breast cancers, the ER-negative phenotype is not the result

Mecanismos de Resistencia Hormonalen Cáncer de Mama

Se hacen

Page 37: Estructura del receptor esteroideo · Mecanismos de Resistencia Hormonal en Cáncer de Mama In the majority of primary breast cancers, the ER-negative phenotype is not the result

Mecanismos de Resistencia Hormonalen Cáncer de Mama

Se hacen

Page 38: Estructura del receptor esteroideo · Mecanismos de Resistencia Hormonal en Cáncer de Mama In the majority of primary breast cancers, the ER-negative phenotype is not the result

Mecanismos de Resistencia Hormonalen Cáncer de Mama

Se hacen

Page 39: Estructura del receptor esteroideo · Mecanismos de Resistencia Hormonal en Cáncer de Mama In the majority of primary breast cancers, the ER-negative phenotype is not the result

Mecanismos de Resistencia Hormonalen Cáncer de Mama

Se hacen

Page 40: Estructura del receptor esteroideo · Mecanismos de Resistencia Hormonal en Cáncer de Mama In the majority of primary breast cancers, the ER-negative phenotype is not the result

Mecanismos de Resistencia Hormonalen Cáncer de Mama

Se hacen

Page 41: Estructura del receptor esteroideo · Mecanismos de Resistencia Hormonal en Cáncer de Mama In the majority of primary breast cancers, the ER-negative phenotype is not the result

Mecanismos de Resistencia Hormonalen Cáncer de Mama

Mutaciones en ESR-1

Page 42: Estructura del receptor esteroideo · Mecanismos de Resistencia Hormonal en Cáncer de Mama In the majority of primary breast cancers, the ER-negative phenotype is not the result

Mecanismos de Resistencia Hormonalen Cáncer de Mama

Page 43: Estructura del receptor esteroideo · Mecanismos de Resistencia Hormonal en Cáncer de Mama In the majority of primary breast cancers, the ER-negative phenotype is not the result

Mecanismos de Resistencia Hormonalen Cáncer de Mama

30 muestras6 modificaciones (3 SNP+ 3 mutaciones)

Analisis funcional in vitro:

Page 44: Estructura del receptor esteroideo · Mecanismos de Resistencia Hormonal en Cáncer de Mama In the majority of primary breast cancers, the ER-negative phenotype is not the result

Mecanismos de Resistencia Hormonalen Cáncer de Mama

Page 45: Estructura del receptor esteroideo · Mecanismos de Resistencia Hormonal en Cáncer de Mama In the majority of primary breast cancers, the ER-negative phenotype is not the result

Mecanismos de Resistencia Hormonalen Cáncer de Mama

Page 46: Estructura del receptor esteroideo · Mecanismos de Resistencia Hormonal en Cáncer de Mama In the majority of primary breast cancers, the ER-negative phenotype is not the result

Mecanismos de Resistencia Hormonalen Cáncer de Mama

Page 47: Estructura del receptor esteroideo · Mecanismos de Resistencia Hormonal en Cáncer de Mama In the majority of primary breast cancers, the ER-negative phenotype is not the result

Mecanismos de Resistencia Hormonalen Cáncer de Mama

Page 48: Estructura del receptor esteroideo · Mecanismos de Resistencia Hormonal en Cáncer de Mama In the majority of primary breast cancers, the ER-negative phenotype is not the result

Mecanismos de Resistencia Hormonalen Cáncer de Mama

Page 49: Estructura del receptor esteroideo · Mecanismos de Resistencia Hormonal en Cáncer de Mama In the majority of primary breast cancers, the ER-negative phenotype is not the result

Mecanismos de Resistencia Hormonalen Cáncer de Mama

Page 50: Estructura del receptor esteroideo · Mecanismos de Resistencia Hormonal en Cáncer de Mama In the majority of primary breast cancers, the ER-negative phenotype is not the result

Mecanismos de Resistencia Hormonalen Cáncer de Mama

Page 51: Estructura del receptor esteroideo · Mecanismos de Resistencia Hormonal en Cáncer de Mama In the majority of primary breast cancers, the ER-negative phenotype is not the result

Mecanismos de Resistencia Hormonalen Cáncer de Mama

FERGIFulvestrant + PictilisibFulvestrant + placebo

Determinación basal ctDNAPI3KESR-1

Page 52: Estructura del receptor esteroideo · Mecanismos de Resistencia Hormonal en Cáncer de Mama In the majority of primary breast cancers, the ER-negative phenotype is not the result

Mecanismos de Resistencia Hormonalen Cáncer de Mama

FERGIFulvestrant + PictilisibFulvestrant + placebo

Determinación basal ctDNAPI3KESR-1

Page 53: Estructura del receptor esteroideo · Mecanismos de Resistencia Hormonal en Cáncer de Mama In the majority of primary breast cancers, the ER-negative phenotype is not the result

Mecanismos de Resistencia Hormonalen Cáncer de Mama

FERGIFulvestrant + PictilisibFulvestrant + placebo

Determinación basal ctDNAPI3KESR-1

Page 54: Estructura del receptor esteroideo · Mecanismos de Resistencia Hormonal en Cáncer de Mama In the majority of primary breast cancers, the ER-negative phenotype is not the result

Mecanismos de Resistencia Hormonalen Cáncer de Mama

Se hacen…

Fenotipo Hormonodependiente Respondedor

Fenotipo Hormonodependiente No Respondedor

Acciones

Tamoxifeno oDeprivación estrogénica

Hipersensibilidad a estrógenos: (Adaptacion celular a responder a bajos niveles de estrógenos)Respuesta a I. Aromatas/Fulvestrant

Deprivación Intensa y Prolongada

Supersensibilidad a estrógenos(Actividad independiente de la unión a ligando)Respuesta a Fulvestrant

Degradación del receptorInsensibilidad a estrógenos(Actividad No genomica)Respuesta a Inh señales celulares)

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