Portal de investigación
NRF2 through RPS6 Activation Is Related to Anti-HER2 Drug Resistance in HER2 -Amplified Gastric Cancer.
Fecha de publicación:
Fecha Ahead of Print:
Autores de INCLIVA
Participantes ajenos a INCLIVA
- Tolosa P
- Cejalvo JM
Grupos y Plataformas de I+D+i
Abstract
Purpose: Despite the clinical advantage of the combination of trastuzumab and platinum-based chemotherapy in HER2-amplified tumors, resistance will eventually develop. The identification of molecular mechanisms related to primary and acquired resistance is needed. Experimental Design: We generated lapatinib- and trastuzumab-resistant clones deriving from two different HER2-amplified gastric cancer cell lines. Molecular changes such as protein expression and gene-expression profile were evaluated to detect alterations that could be related to resistance. Functional studies in vitro were corroborated in vivo. The translational relevance of our findings was verified in a patient cohort. Results: We found RPS6 activation and NRF2 to be related to anti-HER2 drug resistance. RPS6 or NRF2 inhibition with siRNA reduced viability and resistance to anti-HER2 drugs. In knockdown cells for RPS6, a decrease of NRF2 expression was demonstrated, suggesting a potential link between these two proteins. The use of a PI3K/TORC1/TORC2 inhibitor, tested in vitro and in vivo, inhibited pRPS6 and NRF2 expression and caused cell and tumor growth reduction, in anti-HER2-resistant models. In a cohort of HER2-amplified patients treated with trastuzumab and chemotherapy, a high level of NRF2 at baseline corresponds with worse progression-free survival. Conclusions: NRF2 through the PI3K/AKT/mTOR/RPS6 pathway could be a potential effector of resistance to anti-HER2 drugs in our models. RPS6 inhibition decreases NRF2 expression and restores sensitivity in HER2-amplified gastric cancer in vitro and in vivo. High NRF2 expression in gastric cancer patients predicts resistance to treatment. RPS6 and NRF2 inhibition could prevent resistance to anti-HER2 drugs.
© 2018 American Association for Cancer Research.
Datos de la publicación
- ISSN/ISSNe:
- 1078-0432, 1557-3265
- Tipo:
- Article
- Páginas:
- 1639-1649
- PubMed:
- 30504425
CLINICAL CANCER RESEARCH AMER ASSOC CANCER RESEARCH
Citas Recibidas en Web of Science: 59
Documentos
Filiaciones
Financiación
Proyectos y Estudios Clínicos
CONTRATOS RIO HORTEGA
Investigador Principal: NOELIA TARAZONA LLAVERO
CM15/00246 . INSTITUTO SALUD CARLOS III
CONTRATOS JUAN RODES
Investigador Principal: DESAMPARADOS RODA PEREZ
2016/197 . INSTITUTO SALUD CARLOS III . 2017
JR17/00026 AYUDA JOAN RODÉS DRA. TANIA FLEITAS /2017/322)
Investigador Principal: TANIA CAROLINA FLEITAS KANONNIKOFF
JR17/00026 . INSTITUTO SALUD CARLOS III . 2018
Macrófagos asociados al tumor, angiogénesis tumoral y resistencia a las terapias en Cáncer Gástrico Difuso fenotipo Mesenquimal.
Investigador Principal: TANIA CAROLINA FLEITAS KANONNIKOFF
PI18/01508 . INSTITUTO SALUD CARLOS III . 2019
Medicina personalizada en pacientes con cáncer colorrectal localizado: abordaje multiómico de la Enfermedad Mínima Residual en biopsia líquida y modelos de organoides
Investigador Principal: ANDRÉS CERVANTES RUIPEREZ
PI18/01909 . INSTITUTO SALUD CARLOS III . 2019
Cita
Gambardella V,Gimeno F,Tarazona N,Martinez C,Roda D,Fleitas T,Tolosa P,Cejalvo JM,Huerta M,Rosello S,Castillo J,Cervantes A. NRF2 through RPS6 Activation Is Related to Anti-HER2 Drug Resistance in HER2 -Amplified Gastric Cancer. Clin. Cancer Res. 2019. 25. (5):p. 1639-1649. IF:10,107. (1).
NRF2 through RPS6 Activation Is Related to Anti-HER2 Drug Resistance in HER2 -Amplified Gastric Cancer. Gambardella V, Gimeno F, Tarazona N, Martinez C, Roda D, Fleitas T, Tolosa P et al. CLINICAL CANCER RESEARCH. 2019 marzo 01. 25 (5):1639-1649. DOI:10.1158/1078-0432.CCR-18-2421. PMID:30504425.
