Al-hraishawi, Husam Raheem Mohammed. Arsenic may be targeted therapy for cancers harboring trim-domain containing fusion proteins. Retrieved from https://doi.org/doi:10.7282/t3-nx1s-2w86
DescriptionAberrant rearrangements in chromosome structure, leading to oncogenic fusion genes, occur in many hematological and solid tumors. The number of newly identified chromosomal rearrangements has rapidly increased during the past decade because of the widespread use of high-throughput DNA sequencing. Tyrosine kinase fusion result significant subset of oncogenic-rearrangement, which can function as driver oncogenes in multiple human cancers. Cancers harboring fusion genes involving such kinases are often initially highly sensitive to treatment with relevant kinase inhibitors. Unfortunately, resistance to kinase inhibitors almost always develops, highlighting the need for alternative treatment strategies. One approach is also to target the non-kinase partner of these fusion genes. For example, in patients with acute promyelocytic leukemia (APML), which harbors the PML-RARA fusion gene, Arsenic trioxide (ATO) is an effective therapeutic solution. ATO specifically binds a cysteine motif in the PML region of the PML-RAR, leading to poly-SUMOylation and RNF4-mediated ubiquitination and degradation of the fusion protein. The combination of ATO and ATRA targets both the tripartite-motif (TRIM) domain found in the N-terminal of PML (also known as TRIM19), and the C-terminal ligand-binding domain of RARA, respectively, will lead to a long-term cure in the majority of APML patients harboring the fusion gene. Next-generation sequencing of cancers has identified that multiple TRIM family members, such as TRIM24 and TRIM33, are also found to be involved in gene rearrangements with oncogenic kinases in different cancer types, including a novel TRIM33-RET fusion (found in non-small cell lung cancer and thyroid cancer) and TRIM24-BRAF fusion (found in NSCLC as well as in melanoma). Both TRIM33 and TRIM24 also contain similar tripartite motifs found in PML (TRIM19). We hypothesize that ATO can specifically target fusion genes with a conserved TRIM domain for degradation and be part of rationally designed combination therapy for cancers harboring such fusion genes. We have shown with cell-based models that ATO can specifically degrade oncogenic TRIM33-RET fusion protein by RNF4 mediated ubiquitination and degradation. The combination of (As2O3) along with RET kinase inhibitor cabozantinib is more effective than that of cabozantinib alone. Our data provide a novel non-cross resistant strategy to treat a wide set of cancers driven by TRIM-domain containing oncogenic fusions.