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

Abstract

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.

Identification of a cisplatin resistant-based prognostic immune related gene signature in MIBC

“…Further functional experiments in vitro or vivo confirmed that DIAPH3 knockdown could sensitize cisplatin-resistant tumor cells to cisplatin treatment. Moreover, the activation of the NF-kB pathway and EMT pathway have been reported that facilitate the formation of cisplatin resistance [52] , [53] , [54] , [55] , so we explored the relationship between DIAPH3 and these two pathways and found that DIAPH3 knockdown significantly reduced the expression of P-P65, N-cadherin and vimentin. The above results imply that targeting DIAPH3 could be a useful method to reverse cisplatin resistance.…”

Klotho in Cancer: Potential Diagnostic and Prognostic Applications

“…LCTL gene expression was found to be upregulated in triple-negative breast cancer samples, and expression levels correlated with increased cell proliferation, histological grade, and TNM stage [21]. Bladder cancer includes muscleinvasive and non-muscle-invasive forms [57] with distinct biological behavior. Higher γKlotho protein expression was observed in muscle-invasive versus non-muscle-invasive lesions [22].…”