Pharmacological NF-κB inhibition decreases cisplatin chemoresistance in muscle-invasive bladder cancer and reduces cisplatin-induced toxicities.
Rui Miguel Gil da CostaChristine LevesqueDaniella Bianchi-FriasPayel ChatterjeeHung-Ming LamCarlos SantosIlsa M ColemanPedro FerreirinhaManuel VilanovaNazaré Pinto da CunhaHugo CarvalhoAlexandra Moreira-PaisAna Faustino-RochaTiago NetoJosé Batista da CostaJonathan L WrightRita FerreiraPaula A OliveiraJoaquim MendesMargarida M S M BastosBruno ColaçoCarlos LopesPeter C BlackChristopher J SweeneyPeter S NelsonPublished in: Molecular oncology (2023)
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.
Keyphrases
- nuclear factor
- signaling pathway
- lps induced
- toll like receptor
- pi k akt
- oxidative stress
- clinical trial
- muscle invasive bladder cancer
- end stage renal disease
- ejection fraction
- body weight
- newly diagnosed
- chronic kidney disease
- inflammatory response
- randomized controlled trial
- metabolic syndrome
- type diabetes
- machine learning
- physical activity
- hiv infected
- young adults
- mouse model
- dna methylation
- electronic health record
- free survival
- rectal cancer
- artificial intelligence
- high fat diet induced