RET- TRIM33 fuusioproteiinimaligniteetit. Olisiko ATO terapeuttinen?

http://mct.aacrjournals.org/content/14/12_Supplement_2/C133
Tässä artikkelissa pohditaan ATO-terapian mahdollista  merkitystä RET-TRIM33 fuusioproteiini-maligniteetissa.

New Molecular Targets

Abstract C133: Aresenic Trioxide as targeted therapy for cancers harboring TRIM33-RET -fusion proteins

Atul Kulkarni, Jeremy Tang, Kim Hirshfield, Lorna Rodriguez and Shridar Ganesan

DOI: 10.1158/1535-7163.TARG-15-C133 Published December 2015

 Chromosomal rearrangements are genomic events that can result in oncogenic gene fusions that are important drivers of tumorogenesis in multiple human cancers. Gene re-arrangements involving RET proto-oncogene were initially reported in papillary thyroid carcinoma. Recent genomic sequencing analysis have identified several rearrangements involving RET gene in other solid cancer types including lung cancers. The fusion protein resulting from the rearrangements usually contain the intact tyrosine kinase domain of RET fused to a partner protein which provides a constitutive dimerization domain. 

One such rearrangement involved Tripartite repeat motif containing protein 33 (TRIM33) where exons 1-14 of TRIM33 was fused with exon 12-19 of RET which was in frame. Rearrangements involving TRIM33 and RET have been reported in both thyroid cancer and lung cancer. Although these cancers respond to RET inhibitors, the responses are not durable, demonstrating the need for additional treatment approaches to these cancers.

 Arsenic, an ancient drug originally used in traditional Chinese medicine, shows remarkable anticancer activity in patients with acute promyelocytic leukemia (APL) and is now part of the standard therapy of this disease. Several studies have given new insight into the mechanism of action and specificity of AS2O3 in treatment of APL. AS2O3 promotes degradation of fusion protein, PML-RAR α, a fusion protein containing PML zinc finger protein  (TRIM19) and retinoic acid receptor alpha. The protein degradation is triggered by arsenic binding to cysteine residues in RBCC domain of PML and PML-RARα. 

Interestingly PML (TRIM19)  and TRIM33 both belong to same family of TRIM proteins and have highly conserved RBCC domains, suggesting that arsenic may also induced degradation of TRIM33-fusion proteins.

 To evaluate the effect of arsenic trioxide (ATO)  on TRIM33-RET fusion proteins, we first synthesized the in-frame fusion gene, and demonstrated that expression of TRIM33-RET fusion protein in primary cell lines leads to transformation. Cells transformed by TRIM33-RET fusion were highly sensitive to arsenic treatment, compared with similar cells expressing other gene fusions. Acute treatment with arsenic induced ubiquitiylation and degradation of TRIM33-RET fusion protein. The detailed molecular mechanism of arsenic-induced degradation of the TRIM33-RET fusion and possible role of such treatment in treating cancers with such rearrangements will be presented and discussed. 

These data suggest that arsenic trioxide (ATO) , which is now used to target PML-RARa fusion protein in APML, may also be effective in treatment of solid-tumors driven by TRIM33-containing fusion proteins.

Tiedettä RETi RET inhibiittoreista
 https://www.onclive.com/web-exclusives/researcher-highlights-emerging-role-of-ret-inhibitors-in-nsclc?p=2