KIF5B-RET fusion molecules and uses thereof
View Patent ↗Novel RET fusion molecules and uses are disclosed. In one embodiment, a KIF5B-RET fusion includes an in-frame fusion of an exon of KIF5B (e.g., one or more exons encoding a kinesin motor domain or a fragment thereof) and an exon of RET (e.g., one or more exons encoding a RET tyrosine kinase domain or a fragment thereof). For example, the KIF5B-RET fusion can include an in-frame fusion of at least exon 15 of KIF5B or a fragment thereof (e.g., exons 1-15 of KIF5B or a fragment thereof) with at least exon 12 of RET or a fragment thereof (e.g., exons 12-20 of RET or a fragment thereof).
1. A method of treating a subject having a lung cancer or a colorectal cancer, comprising:
responsive to the determination of the presence of a Kinesin Family Member 5B (KIF5B)-RET fusion polypeptide or a nucleic acid molecule encoding the KIF5B-RET fusion polypeptide, administering to the subject an effective amount of a kinase inhibitor or a RET-specific inhibitor,
wherein the KIF5B-RET fusion polypeptide comprises a RET tyrosine kinase domain and a KIF5B kinesin motor domain and coiled-coil domain, of SEQ ID NO:2,
thereby treating the cancer in the subject.
2. The method of claim 1 , wherein said kinase inhibitor is a multi-kinase inhibitor.
3. The method of claim 1 , wherein the kinase inhibitor is chosen from lenvatinib, sorafenib, sunitinib, vandetanib, NVP-AST487, regorafenib, motesanib, cabozantinib, apatinib, or DCC-2157.
4. The method of claim 1 , wherein the presence of the nucleic acid molecule encoding the KIF5B-RET fusion polypeptide is determined by sequencing.
5. The method of claim 1 , wherein said cancer is a colorectal cancer.
6. The method of claim 1 , wherein said cancer is lung cancer.
7. The method of claim 6 , wherein said lung cancer is chosen from: small cell lung cancer (SCLC), adenocarcinoma of the lung, bronchogenic carcinoma, or a combination thereof.
8. The method of claim 6 , wherein the lung cancer is non-small cell lung cancer (NSCLC).
9. The method of claim 6 , wherein the lung cancer is squamous cell carcinoma (SCC).
10. The method of claim 6 , wherein the method comprises administering a multi-kinase inhibitor to the subject.
11. The method of claim 1 , wherein the method comprises administering a RET-specific inhibitor.
12. The method of claim 1 , wherein the kinase inhibitor is sorafenib.
13. The method of claim 1 , wherein the kinase inhibitor is sunitinib.
14. The method of claim 1 , wherein the kinase inhibitor is vandetanib.
15. The method of claim 1 , wherein the kinase inhibitor is NVP-AST487.
16. The method of claim 1 , wherein the kinase inhibitor inhibits the expression of the nucleic acid molecule encoding the KIF5B-RET fusion polypeptide.
17. The method of claim 1 , wherein the kinase inhibitor or RET-specific inhibitor is administered in combination with a second therapeutic agent or a different therapeutic modality.
18. The method of claim 17 , wherein the KIF5B-RET fusion polypeptide or the nucleic acid molecule encoding the KIF5B-RET fusion polypeptide is detected prior to initiating, during, or after, administering the second therapeutic agent or the different therapeutic modality to the subject.
19. The method of claim 1 , wherein the KIF5B-RET fusion polypeptide or the nucleic acid molecule encoding the KIF5B-RET fusion polypeptide is detected at the time of diagnosis with the cancer.
20. The method of claim 1 , wherein said KIF5B-RET fusion polypeptide or nucleic acid molecule encoding said KIF5B-RET fusion polypeptide is an in-frame fusion comprising at least exon 15 of KIF5B and at least exon 12 of RET.
21. The method of claim 1 , wherein said nucleic acid molecule encoding the KIF5B-RET fusion polypeptide comprises nucleotides 1720-1731, 1717-1734, or 1714-1737 of SEQ ID NO:1.
22. The method of claim 1 , wherein the cancer is a lung adenocarcinoma and the kinase inhibitor is cabozantinib.
23. The method of claim 11 , wherein the RET-specific inhibitor is an inhibitor of expression of the nucleic acid molecule encoding the KIF5B-RET fusion polypeptide, or a transcriptional regulatory region that blocks or reduces mRNA expression of the nucleic acid molecule encoding the KIF5B-RET fusion polypeptide.
24. The method of claim 23 , wherein the RET-specific inhibitor is selected from an antisense molecule, a ribozyme, an RNAi molecule, or a triple helix molecule that hybridizes to an encoding region or a transcription regulatory region of said nucleic acid molecule encoding the KIF5B-RET fusion polypeptide thereby blocking or reducing mRNA expression of the nucleic acid molecule encoding the KIF5B-RET fusion polypeptide.
25. The method of claim 11 , wherein the RET-specific inhibitor is a small molecule.
26. A method of treating a subject having lung cancer, comprising:
responsive to the determination of the presence of a Kinesin Family Member 5B (KIF5B)-RET fusion polypeptide or a nucleic acid molecule encoding the KIF5B-RET fusion polypeptide, administering to the subject an effective amount of a kinase inhibitor chosen from sorafenib, sunitinib, vandetanib, or cabozantinib,
wherein the KIF5B-RET fusion polypeptide comprises a RET tyrosine kinase domain and a KIF5B kinesin motor domain and coiled-coil domain, of SEQ ID NO:2,
thereby treating the lung cancer in the subject.
27. A method of treating a subject having lung cancer, comprising:
determining the presence of a Kinesin Family Member 5B (KIF5B)-RET fusion polypeptide or a nucleic acid molecule encoding the KIF5B-RET fusion polypeptide in the subject; and
responsive to the determination of the presence of the KIF5B-RET fusion polypeptide or a nucleic acid molecule encoding the KIF5B-RET fusion polypeptide, administering to the subject an effective amount of a kinase inhibitor chosen from sorafenib, sunitinib, vandetanib, or cabozantinib,
wherein the KIF5B-RET fusion polypeptide comprises a RET tyrosine kinase domain and a KIF5B kinesin motor domain and coiled-coil domain, of SEQ ID NO:2, thereby treating the lung cancer in the subject.