Journal Article

Pharmacological NF‐κB inhibition decreases cisplatin chemoresistance in muscle‐invasive bladder cancer and reduces cisplatin‐induced toxicities

Ferreirinha, Pedro, Mendes, Joaquim, Colaço, Bruno, Pinto da Cunha, Nazaré, Neto, Tiago, Bastos, Margarida M. S. M., Carvalho, Hugo, Bianchi‐Frias, Daniella, Santos, Carlos, Lam, Hung‐Ming, Lopes, Carlos, Wright, Jonathan L., Vilanova, Manuel, Coleman, Ilsa M., Levesque, Christine, Oliveira, Paula A., Nelson, Peter S., Chatterjee, Payel, Faustino‐Rocha, Ana, Batista da Costa, José, Moreira‐Pais, Alexandra, Gil da Costa, Rui M., Black, Peter C., Sweeney, Christopher J., Ferreira, Rita

2023

Overview

Most patients with muscle‐invasive bladder cancer (MIBC) are not cured with platinum chemotherapy. Up‐regulation of nuclear factor kappa light‐chain enhancer of activated B cells (NF‐κB) is a major mechanism underlying chemoresistance, suggesting that its pharmacological inhibition may increase platinum efficacy. NF‐κB signaling was investigated in two patient cohorts. The Cancer Genome Atlas (TCGA) was used to correlate NF‐κB signaling and patient survival. The efficacy of cisplatin plus the NF‐κB inhibitor dimethylaminoparthenolide (DMAPT) versus cisplatin or DMAPT alone was tested in vitro. Xenografted and immunocompetent MIBC mouse models were studied in vivo. Platinum‐naive claudin‐low MIBC showed constitutive NF‐κB signaling and this was associated with reduced disease‐specific survival in TCGA patients. Chemotherapy up‐regulated NF‐κB signaling and chemoresistance‐associated genes, including SPHK1, PLAUR, and SERPINE1. In mice, DMAPT significantly improved the efficacy of cisplatin in both models. The combination preserved body weight, renal function, and morphology, reduced muscle fatigue and IL‐6 serum levels, and did not aggravate immuno‐hematological toxicity compared with cisplatin alone. These data provide a rationale for combining NF‐κB inhibition with platinum‐based chemotherapy and conducting a clinical trial in MIBC patients. NF‐κB up‐regulation promotes chemoresistance of muscle‐invasive bladder cancer (MIBC). The authors showed up‐regulated NF‐κB signaling in therapy‐naive MIBC subsets and post‐chemotherapy MIBC. Combining the NF‐κB inhibitor dimethylaminoparthenolide (DMAPT) with cisplatin therapy increased antitumor efficacy, and prevented cachexia and nephrotoxicity compared with cisplatin alone, without aggravating immuno‐hematological parameters. These data support the combination of NF‐κB inhibition with platinum‐based chemotherapy for MIBC treatment.

• Publisher: John Wiley & Sons, Inc,Wiley
• Subject: Analysis / Animal models / Animals / Antineoplastic Agents - pharmacology / Antineoplastic Agents - therapeutic use / Ataxia / B cells / Bladder cancer / Body weight / Cancer / Cancer therapies / Chemoresistance / Chemotherapy / Cisplatin / Cisplatin - pharmacology / Cisplatin - therapeutic use / Drug Resistance, Neoplasm / Gene expression / Genes / Genetic aspects / Genomes / Genomics / Humans / Invasiveness / Leukocytes / Lymphocytes B / Medical prognosis / Medical research / Medicine, Experimental / Metastasis / Mice / muscle wasting / Muscles / nephrotoxicity / NF-kappa B - genetics / NF-κB protein / parthenolide / Platinum / Renal function / Serum levels / Survival analysis / Toxicity / Tumors / Urinary Bladder Neoplasms - drug therapy / Urinary Bladder Neoplasms - genetics / Urological surgery / Variance analysis