RESUMO
AIMS: Resistance to targeted therapy is one of the critical obstacles in cancer management. Resistance to trastuzumab frequently develops in the treatment for HER2+ cancers. The role of protein tyrosine phosphatases (PTPs) in trastuzumab resistance is not well understood. In this study, we aim to identify pivotal PTPs affecting trastuzumab resistance and devise a novel counteracting strategy. METHODS: Four public datasets were used to screen PTP candidates in relation to trastuzumab responsiveness in HER2+ breast cancer. Tyrosine kinase (TK) arrays were used to identify kinases that linked to protein tyrosine phosphate receptor type O (PTPRO)-enhanced trastuzumab sensitivity. The efficacy of small activating RNA (saRNA) in trastuzumab-conjugated silica nanoparticles was tested for PTPRO upregulation and resistance mitigation in cell models, a transgenic mouse model, and human cancer cell line-derived xenograft models. RESULTS: PTPRO was identified as the key PTP which influences trastuzumab responsiveness and patient survival. PTPRO de-phosphorated several TKs, including the previously overlooked substrate ERBB3, thereby inhibiting multiple oncogenic pathways associated with drug resistance. Notably, PTPRO, previously deemed "undruggable," was effectively upregulated by saRNA-loaded nanoparticles. The upregulated PTPRO simultaneously inhibited ERBB3, ERBB2, and downstream SRC signaling pathways, thereby counteracting trastuzumab resistance. CONCLUSIONS: Antibody-conjugated saRNA represents an innovative approach for targeting "undruggable" PTPs.
Assuntos
Neoplasias da Mama , Resistencia a Medicamentos Antineoplásicos , Nanopartículas , Receptor ErbB-2 , Trastuzumab , Ensaios Antitumorais Modelo de Xenoenxerto , Trastuzumab/farmacologia , Humanos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Animais , Camundongos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Feminino , Receptor ErbB-2/metabolismo , Receptor ErbB-2/antagonistas & inibidores , Linhagem Celular Tumoral , Nanopartículas/química , Camundongos Transgênicos , Antineoplásicos Imunológicos/farmacologia , Proteínas Tirosina Fosfatases Classe 3 Semelhantes a Receptores/metabolismo , Proteínas Tirosina Fosfatases Classe 3 Semelhantes a Receptores/antagonistas & inibidores , Proteínas Tirosina Fosfatases Classe 3 Semelhantes a Receptores/genética , Transdução de Sinais/efeitos dos fármacosRESUMO
Growing evidence for the importance of the gut-brain axis in Parkinson's disease (PD) has attracted researchers' interest in the possible application of microbiota-based treatment approaches. Using a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model, we looked into the prospect of treating PD with fucosylated chondroitin sulfate obtained from sea cucumbers Isostichopus badionotus (fCS-Ib). We showed that giving fCS-Ib polysaccharide orally greatly reduced the motor deficits, dopamine depletion, and alpha-synuclein increase caused by MPTP in the substantia nigra (SN). It appears that the anti-PD action of fCS-Ib polysaccharide could be attained by squelching inflammation. Glial cell hyperactivation in SN and overproduction of proinflammatory substances in serum could both be suppressed by fCS-Ib polysaccharide injection. The bacterial DNA in fresh colonic feces was submitted to 16S rRNA and untargeted metabolic analyses to confirm the participation of the microbiota-gut-brain axis in the aforementioned interpretation. The findings showed that the MPTP treatment-induced decrease in norank_f_Muribaculaceae and the increase in Staphylococcus were reversed by the administration of fCS-Ib polysaccharide. The NF-κB signaling pathway was shown to be involved in the fCS-Ib polysaccharide-induced anti-inflammation. In conclusion, our research demonstrated for the first time how fCS-Ib polysaccharide combats PD by reducing inflammation caused by gut microbial dysbiosis.