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Las alteraciones genéticas inducidas por el cisplatino en KEAP1 promueven la resistencia terapéutica en el carcinoma

Yuki Nakayama¹, Keiko Taguchi², Shun Wakamori¹

¹Department of Biochemistry and Molecular Biology, Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan; Department of Otorhinolaryngology-Head and Neck Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan.

|August 20, 2025

Resumen

La resistencia al cisplatino en el cáncer de cabeza y cuello está relacionada con el sistema KEAP1-NRF2. Dirigirse a esta vía con Mitomycin C es prometedor para el tratamiento de tumores resistentes.

Área de la Ciencia:

En el campo de la oncología
Biología molecular
Investigación del cáncer

Sus antecedentes:

La resistencia al cisplatino (CDDP) es un obstáculo significativo en el tratamiento del carcinoma de células escamosas de cabeza y cuello (HNSCC) recurrente.
La vía KEAP1-NRF2 regula el equilibrio redox celular y a menudo se altera en los cánceres, pero su papel en la resistencia adquirida a CDDP en HNSCC no se comprende completamente.

Objetivo del estudio:

Investigar el papel de la activación del NRF2 en la resistencia al CDDP en el HNSCC.
Explorar las posibles estrategias terapéuticas dirigidas al HNSCC activado por NRF2.

Principales métodos:

Se utilizaron siete líneas celulares parentales (P) de HNSCC y sus derivados resistentes al CDDP (CR).
Se analizaron la expresión de NRF2, las mutaciones KEAP1/NFE2L2 y la expresión del gen diana de NRF2.
Se evaluó la citotoxicidad de la mitomicina C (MMC) en líneas CR altas en NRF2.
Se realizó un análisis inmunohistoquímico en muestras clínicas de HNSCC.

Principales resultados:

Tres de las líneas CR HNSCC mostraron una expresión elevada de NRF2, dos con mutaciones KEAP1 y una con mutación NFE2L2.
Las líneas CR altas en NRF2 exhibieron genes diana de NRF2 regulados al alza y vías enriquecidas en el metabolismo xenobiótico y las especies reactivas de oxígeno.
La mitomicina C demostró una potente citotoxicidad específicamente en líneas CR con alto NRF2.
La alta expresión de NRF2 en muestras clínicas se correlacionó significativamente con un mal pronóstico y la recurrencia después de la quimioradioterapia basada en CDDP.

Conclusiones:

La resistencia adquirida al CDDP en HNSCC puede estar asociada con la activación aberrante del eje KEAP1-NRF2.
Esta activación del NRF2 promueve la progresión tumoral y la resistencia terapéutica.
El HNSCC hiperactivado por NRF2 presenta una vulnerabilidad que puede ser explotada por el tratamiento con Mitomicina C.

Palabras clave:

El cisplatino Carcinoma de células escamosas de la cabeza y el cuello El objetivo de este proyecto es:Mitomicina C y sus derivados En el caso de las personas físicas

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