ALK and NTRK1 fusion molecules and uses thereof

1. A method of treating a subject having a cancer, comprising:

identifying the cancer as having an LMNA-NTRK1 fusion polypeptide or a nucleic acid molecule encoding an LMNA-NTRK1 fusion polypeptide; and

administering to the subject an effective amount of an anti-cancer agent, thereby treating the cancer in the subject, wherein:

the LMNA-NTRK1 fusion polypeptide comprises amino acids 1-171 of SEQ ID NO: 10 or a fragment thereof, or an amino acid sequence at least 85% identical thereto, and amino acids 289-560 of SEQ ID NO: 10 or a fragment thereof, or an amino acid sequence at least 85% identical thereto, and

wherein the cancer is chosen from a Spitz tumor, a melanoma, a colorectal cancer, a pancreatic cancer, a thyroid cancer, a breast cancer or, a histiocytic cancer.

2. The method of claim 1 , wherein said anti-cancer agent is a kinase inhibitor.

3. The method of claim 1 , wherein the cancer is identified as having the nucleic acid molecule encoding the LMNA-NTRK1 fusion polypeptide by a sequencing method.

4. The method of claim 1 , wherein the anti-cancer agent is chosen from: lestaurtinib (CEP-701), axitinib (AG013736), bosutinib (SKI-606), cediranib (AZD2171), dasatinib (BMS-354825), erlotinib, gefitinib, imatinib (CGP57148B or STI-571), lapatinib, neratinib (HKI-272), nilotinib, semaxanib (semaxinib or SU5416), sunitinib (SU11248), toceranib, vandetanib, vatalanib (PTK787 or PTK/ZK), sorafenib, ENMD-2076, PCI-32765, AC220, dovitinib lactate (TKI258 or CHIR-258), BIBW 2992, SGX523, PF-04217903, PF-02341066, PF-299804, BMS-777607, ABT-869, MP470, BIBF 1120, AP24534, JNJ-26483327, MGCD265, DCC-2036, BMS-690154, CEP-11981, tivozanib (AV-951), OSI-930, MM-121, XL-184, XL-647, XL228, an ALK-specific inhibitor, TAE-684, PF02341066 (crizotinib), AF-802, LDK-378, ASP-3026, CEP-37440, CEP-28122, CEP-108050, or AP26113; or

an inhibitor that is chosen from an antisense molecule, a ribozyme, an RNAi molecule, or a triple helix molecule and that hybridizes to the nucleic acid molecule encoding the LMNA-NTRK1 fusion polypeptide or hybridizes to a transcription regulatory region thereby blocking or reducing mRNA expression of the nucleic acid molecule encoding the LMNA-NTRK1 fusion polypeptide.

5. The method of claim 2 , wherein the kinase inhibitor is administered in combination with a second therapeutic agent or a different therapeutic modality.

6. The method of claim 5 , wherein the second therapeutic agent is a cytotoxic agent or a cytostatic agent.

7. The method of claim 6 , wherein the cytotoxic agent is chosen from: an antimicrotubule agent, a topoisomerase inhibitor, a taxane, an antimetabolite, a mitotic inhibitor, an alkylating agent, an intercalating agent, an agent capable of interfering with a signal transduction pathway, an agent that promotes apoptosis, or radiation.

8. The method of claim 5 , wherein the second therapeutic agent is an immunomodulatory agent.

9. The method of claim 8 , wherein the immunomodulatory agent is chosen from: IL-1, IL-2, IL-4, IL-6, IL-12, interferon alpha, interferon gamma, an immune cell growth factor, or GM-CSF.

10. The method of claim 1 , wherein the nucleic acid molecule encoding the LMNA-NTRK1 fusion polypeptide comprises an in-frame fusion of a fragment comprising nucleotides 1-513 of SEQ ID NO: 9, or a nucleotide sequence at least 85% identical thereto, and a fragment comprising nucleotides 867-1680 of SEQ ID NO: 9, or a nucleotide sequence at least 85% identical thereto.

11. The method of claim 1 , wherein the nucleic acid molecule encoding the LMNA-NTRK1 fusion polypeptide comprises an in-frame fusion of at least the nucleotide sequence of exon 2 of LMNA of SEQ ID NO: 9, and a fragment comprising nucleotides 867-1680 of SEQ ID NO: 9.

12. The method of claim 1 , wherein the nucleic acid molecule encoding the LMNA-NTRK1 fusion polypeptide comprises a break point comprising the nucleotide sequence of SEQ ID NO: 8 or a fragment thereof.

13. The method of claim 1 , wherein the LMNA-NTRK1 fusion polypeptide comprises amino acids 1-171 and 289-560 of SEQ ID NO: 10.

14. A method of treating a subject having a cancer, comprising:

identifying the cancer as having an LMNA-NTRK1 fusion polypeptide or a nucleic acid molecule encoding an LMNA-NTRK1 fusion polypeptide; and

administering to the subject an effective amount of a kinase inhibitor,

thereby treating the cancer in the subject,

wherein the LMNA-NTRK1 fusion polypeptide comprises amino acids 1-171 of SEQ ID NO: 10, or an amino acid sequence at least 85% identical thereto, and amino acids 289-560 of SEQ ID NO: 10, or an amino acid sequence at least 85% identical thereto, and

wherein said cancer is chosen from a Spitz tumor, a melanoma, a colorectal cancer, a pancreatic cancer, a thyroid cancer, a breast cancer or, a histiocytic cancer.

15. The method of claim 14 , wherein the cancer is identified as having the nucleic acid molecule encoding the LMNA-NTRK1 fusion polypeptide by a sequencing method.

16. The method of claim 14 , wherein the nucleic acid molecule encoding the LMNA-NTRK1 fusion polypeptide comprises an in-frame fusion of a fragment comprising nucleotides 1-513 of SEQ ID NO: 9, or a nucleotide sequence at least 85% identical thereto, and a fragment comprising nucleotides 867-1680 of SEQ ID NO: 9, or a nucleotide sequence at least 85% identical thereto.

17. The method of claim 14 , wherein the nucleic acid molecule encoding the LMNA-NTRK1 fusion polypeptide comprises an in-frame fusion of at least the nucleotide sequence of exon 2 of LMNA of SEQ ID NO: 9, and a fragment comprising nucleotides 867-1680 of SEQ ID NO: 9.

18. The method of claim 14 , wherein the nucleic acid molecule encoding the LMNA-NTRK1 fusion polypeptide comprises a break point comprising the nucleotide sequence of SEQ ID NO: 8 or a fragment thereof.

19. The method of claim 14 , wherein the LMNA-NTRK1 fusion polypeptide comprises amino acids 1-171 and 289-560 of SEQ ID NO: 10.

20. The method of claim 1 , wherein the anti-cancer agent is a multi-kinase inhibitor.

21. The method of claim 14 , wherein the kinase inhibitor is a multi-kinase inhibitor.

22. A method of treating a subject having a colorectal cancer, comprising:

identifying the colorectal cancer as having an LMNA-NTRK1 fusion polypeptide or a nucleic acid molecule encoding an LMNA-NTRK1 fusion polypeptide; and

administering to the subject an effective amount of a kinase inhibitor,

thereby treating the colorectal cancer in the subject,

wherein the LMNA-NTRK1 fusion polypeptide comprises amino acids 1-171 of SEQ ID NO: 10 or a fragment thereof, or a sequence at least 85% identical thereto, and amino acids 289-560 of SEQ ID NO: 10 or a fragment thereof, or a sequence at least 85% identical thereto.

23. The method of claim 1 , wherein the LMNA-NTRK1 fusion polypeptide comprises an NTRK1 receptor tyrosine kinase domain or a functional fragment thereof.

24. The method of claim 1 , wherein the LMNA-NTRK1 fusion polypeptide has an elevated receptor tyrosine kinase activity as compared with wild-type NTRK1.

25. The method of claim 1 , wherein the LMNA-NTRK1 fusion polypeptide comprises the amino acid sequence of SEQ ID NO: 10 or an amino acid sequence at least 85% identical thereto.

26. The method of claim 1 , wherein the LMNA-NTRK1 fusion polypeptide is encoded by the nucleotide sequence of SEQ ID NO: 9 or a nucleotide sequence at least 85% identical thereto.

27. The method of claim 1 , wherein the anti-cancer agent is lestaurtinib (CEP-701).

28. The method of claim 14 , wherein the LMNA-NTRK1 fusion polypeptide comprises an NTRK1 receptor tyrosine kinase domain or a functional fragment thereof.

29. The method of claim 14 , wherein the LMNA-NTRK1 fusion polypeptide has an elevated receptor tyrosine kinase activity as compared with wild-type NTRK1.

30. The method of claim 14 , wherein the LMNA-NTRK1 fusion polypeptide comprises the amino acid sequence of SEQ ID NO: 10 or an amino acid sequence at least 85% identical thereto.

31. The method of claim 14 , wherein the LMNA-NTRK1 fusion polypeptide is encoded by the nucleotide sequence of SEQ ID NO: 9 or a nucleotide sequence at least 85% identical thereto.

32. The method of claim 14 , wherein the kinase inhibitor is lestaurtinib (CEP-701).

33. The method of claim 22 , wherein the LMNA-NTRK1 fusion polypeptide comprises an NTRK1 receptor tyrosine kinase domain or a functional fragment thereof.

34. The method of claim 22 , wherein the LMNA-NTRK1 fusion polypeptide has an elevated receptor tyrosine kinase activity as compared with wild-type NTRK1.

35. The method of claim 22 , wherein the LMNA-NTRK1 fusion polypeptide comprises the amino acid sequence of SEQ ID NO: 10 or an amino acid sequence at least 85% identical thereto.

36. The method of claim 22 , wherein the LMNA-NTRK1 fusion polypeptide is encoded by the nucleotide sequence of SEQ ID NO: 9 or a nucleotide sequence at least 85% identical thereto.

37. The method of claim 22 , wherein the kinase inhibitor is lestaurtinib (CEP-701).