Identification and characterization of novel targets in Papillary Thyroid Cancer (PTC)
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Abstract
Papillary thyroid cancer (PTC) is the most common type of endocrine cancer. Partial or
complete removal of the thyroid lobe, followed by radioactive iodine treatment (131I)
(RAI) is the standard treatment strategy for the treatment of thyroid cancer. But the
management of tumors that cannot undergo resection, mostly due to distant metastasis
and/or development of resistance to RAI is challenging. Identifying and understanding
the molecular pathogenesis underlying thyroid cancer is important for the development
of better diagnosis and treatment. The main aim of the project is the identification and
validation of novel molecular alterations in PTC patient samples by employing
genomic and proteomic approaches.
From a set of patients whose PTC did not harbour any BRAF or RAS mutations (the
most common mutations in PTC), a 35 years old male patient’s normal, primary tumor
and metastatic tissues were selected for both genomic and proteomic analysis. We
identified a novel RET gene fusion in this patient and the oncogenic ability of this novel
gene fusion was tested in transformation assays. Stable expression of the novel RET
fusion gene activated several oncogenic signalling pathways and transformed
immortalized human thyroid cells. The novel RET fusion exhibited high kinase activity
and formed dimers and oligomers partially in a PB1 domain dependent manner.
Quantitative proteomic analysis of normal vs tumour vs metastasis of the same patient
revealed the upregulation of proteins involved in the ubiquitination machinery including
HECT carrying E3 ligase HUWE1 and Deubiquitinating enzymes (DUBs) like USP9X
and UBP7 in the tumour and metastatic lesions. Inhibition of RET, HUWE1 and DUBs
by small molecule inhibitors significantly reduced RET-mediated oncogenesis. Apart
from unveiling a novel oncogenic RET fusion in PTCs, our data opens a novel avenue
of targeting ubiquitin signalling machinery in human PTCs.