Proteogenomics analysis unveils a TFG-RET gene fusion and druggable targets in papillary thyroid carcinomas

Abstract

Papillary thyroid cancer (PTC) is the most common type of endocrine malignancy. By RNAseq analysis, we identify a RET rearrangement in the tumour material of a patient who does not harbour any known RAS or BRAF mutations. This new gene fusion involves exons 1-4 from the 5′ end of the Trk fused Gene (TFG) fused to the 3′ end of RET tyrosine kinase leading to a TFG-RET fusion which transforms immortalized human thyroid cells in a kinasedependent manner. TFG-RET oligomerises in a PB1 domain-dependent manner and oligomerisation of TFG-RET is required for oncogenic transformation. Quantitative proteomic analysis reveals the upregulation of E3 Ubiquitin ligase HUWE1 and DUBs like USP9X and UBP7 in both tumor and metastatic lesions, which is further confirmed in additional patients. Expression of TFG-RET leads to the upregulation of HUWE1 and inhibition of HUWE1 significantly reduces RET-mediated oncogenesis.

State of the Art in the Current Management and Future Directions of Targeted Therapy for Differentiated Thyroid Cancer

“…It results from the merging of RET gene segment with a different pair gene, thus leading to excessive activation of MAPK and PI3K/mTOR/AKT pathways [ 147 ]. RET/PTC generates oncogenic fusion proteins, more frequently in younger patients and associated with DNA damage after ionizing radiation (e.g., up to 60% cases of post-Chernobyl PTCs) [ 148 , 149 ].…”

The E3 ligase HUWE1 inhibition as a therapeutic strategy to target MYC in multiple myeloma

“…To determine whether HUWE1 has any functional significance in MM, we first analyzed the effect of small molecule inhibition or shRNA knockdown of HUWE1 on the growth and survival of MM cell lines. HUWE1 inhibitors BI8622 and BI8626 have been previously identified and characterized [16,25]. Inhibition of HUWE1 autoubiquitination confirmed on-target activity of the inhibitors ( Supplementary Fig.…”

Investigating natural compounds against oncogenic RET tyrosine kinase using pharmacoinformatic approaches for cancer therapeutics

“…7 Oncogenic activation of RET can also occur via chromosomal rearrangements producing hybrid proteins that combines RET kinase domain with another protein containing a dimerization domain. 10 The abnormal expression of RET has been implicated in several human disorders including Hirschsprung's disease, [11][12][13] multiple endocrine neoplasias type 2A (MEN2A) and 2B (MEN2B), 12,14,15 non-small cell lung cancer (NSCLC) as well as papillary (PTC) 12,16 and medullary thyroid cancers (MTC). 12,17 Oncogenic RET activity is also observed in numerous cancer types such as prostate, 18 colorectal, 19 pancreatic, 20 breast 21 and glioblastomas.…”