Suppression of TLR signaling by IRAK-1 and -4 dual inhibitor decreases TPF-resistance-induced pro-oncogenic effects in HNSCC.
Humayara KhanSachchida Nand PandeyAbhishek MishraRatika SrivastavaPublished in: 3 Biotech (2022)
Combination of docetaxel, cisplatin and 5-FU, known as TPF, is an FDA-approved treatment for head and neck squamous cell carcinoma (HNSCC). Acquired chemo-resistance to TPF, a primary reason for non-responsiveness to the treatment and relapse of tumor is a major concern for treatment failure, especially in elder patients. In this study, we investigated the role of Interleukin-1 receptor-associated kinases (IRAK) mediated Toll-like receptor (TLR)-signaling in chemo-resistance using a cell line-based in-vitro TPF-resistant HNSCC model of laryngeal origin. TPF chemo-resistant state showed over-expression and phosphorylation of the active downstream kinases IRAK-1 and IRAK-4 along with enhanced proliferative potential, survival, stemness and metastatic capability as compared to the parent cell line. Pharmacological inhibition of IRAK-1 and -4 had a cytostatic effect on chemo-resistant cells and re-sensitized them to chemotherapy. The treatment also decreased the pro-oncogenic effects of the chemo-resistant cells. Our study provides insights into the pro-oncogenic role of amplified IRAK-1 and-4 mediated TLR signaling in TPF-resistant HNSCC. Pharmacological inhibition of IRAK-1 and-4 signaling is a promising therapeutic strategy for TPF-resistant HNSCC. It can also be used as a combination therapy or a chemo-drug sparing regimen in HNSCC.
Keyphrases
- combination therapy
- toll like receptor
- photodynamic therapy
- locally advanced
- immune response
- inflammatory response
- squamous cell carcinoma
- stem cells
- nuclear factor
- small cell lung cancer
- emergency department
- rectal cancer
- poor prognosis
- cell proliferation
- ejection fraction
- radiation therapy
- prognostic factors
- cell death
- drug delivery
- climate change
- human health
- adverse drug
- diabetic rats