With two ROS1-positive patients remaining on treatment for more than 2 years, we believe the results we announced today further distinguish repotrectinib, and are supportive of our ongoing, multi-cohort registrational Phase 2 TRIDENT-1 Study."With TPX-0046, we have demonstrated strong preclinical potency in Ba/F3 cells with the mutated KIF5B
RET fusion gene and against multiple solvent front mutations that may arise from other investigational RET inhibitors and lead to treatment resistance.
[21.] Ma H, Cai Q, Lu W, Sheng ZH, Mochida S (2009) KIF5B
motor adaptor syntabulin maintains synaptic transmission in sympathetic neurons.
* RET fusion variants KIF5B
(K15:R12, K16:R12, K22:R12, K23:R12, K24:R11, K24:R8); CCDC6 (C1:R12); TRIM33 (T14:R12): Patients with mutations in this oncogene may benefit from treatment with cabozantinib or vandetinib.
For RET-positive patients, kinesin family member 5B (KIF5B
) and coiled-coil domain containing 6 (CCDC6) were the partners identified.
Ambrosio, "Diabetes induces changes in KIF1A, KIF5B
and dynein distribution in the rat retina: Implications for axonal transport," Experimental eye Research, vol.
Ferreira, "The docking of kinesins, KIF5B
and KIF5C, to ran-binding protein 2 (RanBP2) is mediated via a novel RanBP2 domain," The Journal of Biological Chemistry, vol.
In mammalian axons of neuronal cells, mitochondrial movement from the cell body to the synaptic junctions (known as anterograde movement) is driven by the kinesin-1 motor (KHC, Kif5b
) and movement from the synaptic junctions to the cell body (the retrograde movement) is driven by dynein, whereas in yeast the transport is based on actin [182, 183].
Elvas et al., "Diabetes alters KIF1A and KIF5B
motor proteins in the hippocampus," PLoS ONE, vol.
Recent research has also revealed that RET and KIF5B
gene fusion (gene mutation) occurs in some lung cancer patients, which means that RET tyrosine kinase inhibitors may potentially be used in the treatment of lung cancer patients with this gene mutation.
(12) In addition to EML4, less common fusion partners have been described, including TRK-fused gene (TFG), kinesin light chain 1 (KLC1), and kinesin family member 5B (KIF5B
), although the clinical relevance of the different fusion partners is unknown.
Furthermore, in addition to EML4, other ALK fusion partners have been reported, such as TRK-fused gene (TGF), kinesin family member 5B (KIF5B
), and kinesin light chain 1 (KLC1).
As with ALK and ROS1 rearrangements, RET is activated by rearrangements that fuse the tyrosine kinase domain of RET with coiled-coil dimerization domains of one of a variety of recurring partner genes, including KIF5B
(the most common, at 90%), (64,72,73) CCDC6, (65,74) NCOA (4,62) and TRIM33.