ABSTRACT
Chemotherapy in combination with immunotherapy has gradually shown substantial promise to increase T cell infiltration and antitumor efficacy. However, paclitaxel in combination with immune checkpoint inhibitor targeting PD-1/PD-L1 was only used to treat a small proportion of metastatic triple-negative breast cancer (TNBC), and the clinical outcomes was very limited. In addition, this regimen cannot prevent paclitaxel-induced peripheral neuropathy. Therefore, there was an urgent need for a novel target to enhance the antitumor activity of paclitaxel and alleviate chemotherapy-induced peripheral neuropathy in breast cancer. Here, we found that Dickkopf-1 (DKK1) expression was upregulated in multiply subtypes of human breast cancer specimens after paclitaxel-based chemotherapy. Mechanistic studies revealed that paclitaxel promoted DKK1 expression by inducing EGFR signaling in breast cancer cells, and the upregulation of DKK1 could hinder the therapeutic efficacy of paclitaxel by suppressing the infiltration and activity of CD8+ T cells in tumor microenvironment. Moreover, paclitaxel treatment in tumor-bearing mice also increased DKK1 expression through the activation of EGFR signaling in the primary sensory dorsal root ganglion (DRG) neurons, leading to the development of peripheral neuropathy, which is charactered by myelin damage in the sciatic nerve, neuropathic pain, and loss of cutaneous innervation in hindpaw skin. The addition of an anti-DKK1 antibody not only improved therapeutic efficacy of paclitaxel in two murine subtype models of breast cancer but also alleviated paclitaxel-induced peripheral neuropathy. Taken together, our findings providing a potential chemoimmunotherapy strategy with low neurotoxicity that can benefit multiple subtypes of breast cancer patients.
Subject(s)
Intercellular Signaling Peptides and Proteins , Paclitaxel , Peripheral Nervous System Diseases , Paclitaxel/adverse effects , Paclitaxel/pharmacology , Intercellular Signaling Peptides and Proteins/metabolism , Intercellular Signaling Peptides and Proteins/genetics , Humans , Animals , Peripheral Nervous System Diseases/chemically induced , Female , Mice , Cell Line, Tumor , ErbB Receptors/metabolism , Tumor Microenvironment/drug effects , Xenograft Model Antitumor Assays , Breast Neoplasms/drug therapy , Breast Neoplasms/pathology , Breast Neoplasms/metabolism , Signal Transduction/drug effects , Gene Expression Regulation, Neoplastic/drug effects , Triple Negative Breast Neoplasms/drug therapy , Triple Negative Breast Neoplasms/pathology , Triple Negative Breast Neoplasms/metabolismABSTRACT
Alport syndrome (AS), a hereditary kidney disease with a high risk for renal failure, is attributed to pathogenic variants in genes COL4A3, COL4A4, and COL4A5 that encode type IV collagen. Next-generation sequencing (NGS) is increasingly applied to the diagnosis of AS, but complex genotype-phenotype correlation, that is, identifying the significance of variants, is still a huge clinical challenge. In this study, we reported the case of a 27-year-old Chinese woman with a family history of hematuria and proteinuria. Notably, the proband is the only one in her family with renal insufficiency. NGS was performed in this family, and it was revealed that the proband was a compound heterozygote for two variants in the COL4A3 gene: c.2990G>A inherited from her father and c.4981C>T inherited from her mother. We modeled the spatial structure of the corresponding protein and assumed that structural abnormalities led to the breakdown of type IV collagen networks, a major component of the glomerular basement membrane. Thus, the proband was diagnosed with autosomal recessive AS, characterized by severe defects of the glomerular basement membrane. Hence, the proband showed a loss of renal function. This case presentation emphasizes the importance of NGS for AS diagnosis and introduces a novel genotype of AS.