Methods of treating urothelial carcinoma

1. A method of treating a subject having a micropapillary urothelial or a bladder carcinoma that lacks HER2 gene amplification, comprising:

(i) identifying the carcinoma as having a HER2 kinase activating mutation in the extracellular domain at residue 310 or at residue 157 of HER2;

(ii) identifying the carcinoma as having a micropapillary histology; and

(iii) administering to the subject an effective amount of an agent that inhibits HER2 expression or activity, thereby treating the carcinoma.

2. The method of claim 1 , wherein the subject is a human.

3. The method of claim 1 , wherein the subject does not have, or is identified as not having, an elevated level of a HER2 gene product.

4. The method of claim 1 , wherein the HER2 kinase activating mutation is chosen from:

(i) a substitution at residue 310 of HER2;

(ii) a substitution of a serine residue at position 310 (S310) of HER2 to phenylalanine;

(iii) a substitution of a serine residue at position 310 (S310) of HER2 to tyrosine;

(iv) a substitution at residue 157; or

(v) a substitution of an arginine residue at position 157 (R157) of HER2 to tryptophan.

5. The method of claim 1 , wherein the subject is undergoing or has undergone a treatment with a non-HER2 therapeutic agent or therapeutic modality.

6. The method of claim 5 , wherein the non-HER2 therapeutic agent or therapeutic modality comprises one or more of: methotrexate, vinblastine, doxorubicin, or cisplatin.

7. The method of claim 5 , wherein, responsive to a determination of the presence of the HER2 kinase activating mutation, the non-HER2 therapeutic agent or therapeutic modality is discontinued.

8. The method of claim 5 , wherein the agent that inhibits HER2 expression or activity is administered after cessation of the non-HER2 therapeutic agent or therapeutic modality.

9. The method of claim 1 , wherein the agent that inhibits HER2 expression or activity is chosen from one or more of: a kinase inhibitor; a multi-specific kinase inhibitor; a HER2-specific inhibitor; an EGFR inhibitor; a reversible or an irreversible HER2 inhibitor; a pan ERBB inhibitor; a small molecule inhibitor that is selective for HER2; an antibody molecule; a monoclonal or a bispecific antibody against HER2; an antibody to HER2 conjugated to a cytotoxic agent; or a HER2 cellular immunotherapy.

10. The method of claim 1 , wherein the agent that inhibits HER2 expression or activity is an anti-HER2 antibody molecule, or a conjugate thereof.

11. The method of claim 1 , wherein the agent that inhibits HER2 expression or activity is chosen from one or more of: AV-203, AMG 888, U3-1287, APC8024, DN24-02, Neuvenge, Lapuleucel-T, MM-111, MM-121, SAR256212, MM-141, LJM716, REGN1400, MEHD7945A, RG7597, RG7116, Trastuzumab, trastuzumab emtansine (T-DM1), pertuzumab, afatinib, TAK-285, Neratinib, Dacomitinib, BMS-690514, BMS-599626, Pelitinib, CP-724714, Lapatinib, TAK-165, ARRY-380, AZD8931, or Neratinib.

12. The method of claim 1 , wherein the HER2 comprises the amino acid sequence of SEQ ID NO: 1.

13. The method of claim 3 , wherein the subject does not have an elevated level of a HER2 gene product.

14. The method of claim 3 , wherein the subject is identified as not having an elevated level of a HER2 gene product.

15. The method of claim 4 , wherein the HER2 kinase activating mutation is a substitution at residue 157 of HER2.

16. A method of treating a subject having a micropapillary carcinoma that lacks HER2 gene amplification, comprising administering to the subject an effective amount of an agent that inhibits HER2 expression or activity, wherein:

(i) the carcinoma has a HER2 kinase activating mutation at residue 310 or residue 157 of HER2; and

(ii) the carcinoma is chosen from a cancer of the urinary tract, bladder, or urothelial cells,

thereby treating the carcinoma.

17. The method of claim 16 , wherein the subject does not have a gene amplification or overexpression of HER2 or a HER2 gene product.

18. The method of claim 16 , wherein the subject is identified as not having a gene amplification or overexpression of HER2 or a HER2 gene product.

19. The method of claim 16 , wherein the subject does not have, or is identified as not having, an elevated level of a HER2 gene product.

20. The method of claim 16 , wherein the subject is a human.

21. The method of claim 16 , wherein the subject is undergoing or has undergone treatment with a non-HER2 therapeutic agent or therapeutic modality that comprises one or more of: methotrexate, vinblastine, doxorubicin, or cisplatin.

22. The method of claim 21 , wherein, responsive to the determination of the presence of one or both of the HER2 kinase activating mutation or a micropapillary histology in the carcinoma, the non-HER2 therapeutic agent or therapeutic modality is discontinued.

23. The method of claim 21 , wherein the agent that inhibits HER2 expression or activity is administered after cessation of the non-HER2 therapeutic agent or therapeutic modality.

24. The method of claim 16 , wherein the agent that inhibits HER2 expression or activity is chosen from one or more of: a kinase inhibitor; a multi-specific kinase inhibitor; a HER2-specific inhibitor; an EGFR inhibitor; a reversible or an irreversible HER2 inhibitor; a pan ERBB inhibitor; a small molecule inhibitor that is selective for HER2; an antibody molecule; a monoclonal or a bispecific antibody against HER2; an antibody to HER2 conjugated to a cytotoxic agent; or a HER2 cellular immunotherapy.

25. The method of claim 16 , wherein the agent that inhibits HER2 expression or activity is an anti-HER2 antibody molecule, or a conjugate thereof.

26. The method of claim 16 , wherein the agent that inhibits HER2 expression or activity is chosen from one or more of: AV-203, AMG 888, U3-1287, APC8024, DN24-02, Neuvenge, Lapuleucel-T, MM-111, MM-121, SAR256212, MM-141, LJM716, REGN1400, MEHD7945A, RG7597, RG7116, Trastuzumab, trastuzumab emtansine (T-DM1), pertuzumab, afatinib, TAK-285, Neratinib, Dacomitinib, BMS-690514, BMS-599626, Pelitinib, CP-724714, Lapatinib, TAK-165, ARRY-380, AZD8931, or Neratinib.

27. The method of claim 16 , wherein the agent that inhibits HER2 expression or activity is chosen from an antisense molecule, a ribozyme, a double stranded RNA, or a triple helix molecule, wherein the agent hybridizes to and/or inhibits a HER2 nucleic acid, or a transcription regulatory region that blocks or reduces mRNA expression of the nucleic acid encoding a HER2 gene product with a HER2 kinase activating mutation.

28. The method of claim 16 , wherein the HER2 kinase activating mutation is detected by sequencing.

29. The method of claim 16 , wherein the HER2 kinase activating mutation is detected in a nucleic acid molecule acquired from the subject, wherein said nucleic acid molecule is present in a circulating cell; a urothelial or micropapillary carcinoma; or a blood or plasma sample.

30. The method of claim 16 , wherein the HER2 kinase activating mutation is chosen from:

(i) a substitution at residue 310 of HER2;

(ii) a substitution of a serine residue at position 310 (S310) of HER2 to phenylalanine or tyrosine of HER2;

(iii) a substitution at residue 157 of HER2; or

(iv) a substitution of an arginine residue at position 157 (R157) of HER2 to tryptophan,

wherein the HER2 comprises the amino acid sequence of SEQ ID NO:1.

31. The method of claim 30 , wherein the HER2 kinase activating mutation is a substitution of a serine residue at position 310 (S310) of HER2 to phenylalanine or tyrosine.

32. The method of claim 31 , wherein the HER2 kinase activating mutation is detected by sequencing.

33. The method of claim 30 , wherein the agent that inhibits HER2 expression or activity is administered responsive to a determination of the presence of the HER2 kinase activating mutation in the carcinoma.

34. The method of claim 30 , wherein the HER2 kinase activating mutation is detected in a nucleic acid molecule acquired from the subject, wherein said nucleic acid molecule is present in a circulating cell, a urothelial or micropapillary carcinoma, or a blood or plasma sample.

35. The method of claim 30 , wherein the HER2 kinase activating mutation is a substitution at residue 310 of HER2.

36. The method of claim 16 , wherein the HER2 kinase activating mutation is a substitution at residue 310 of HER2.

37. The method of claim 16 , wherein the HER2 kinase activating mutation is a substitution at residue 157 of HER2.

38. A method of treating a subject having a micropapillary carcinoma chosen from a cancer of the urinary tract, bladder, or urothelial cells, said method comprising:

(i) identifying the carcinoma as having a HER2 kinase activating mutation in the extracellular domain at residue 310 or at residue 157 of HER2; and

(ii) administering to the subject an effective amount of an agent that inhibits HER2, wherein the agent is chosen from one or more of a kinase inhibitor, an antibody molecule, or a HER2 cellular immunotherapy; and

wherein the carcinoma does not have an elevated level of a HER2 gene product,

thereby treating the micropapillary carcinoma.

39. The method of claim 38 , wherein the agent that inhibits HER2 is chosen from one or more of: AV-203, AMG 888, U3-1287, APC8024, DN24-02, Neuvenge, Lapuleucel-T, MM-111, MM-121, SAR256212, MM-141, LJM716, REGN1400, MEHD7945A, RG7597, RG7116, Trastuzumab, trastuzumab emtansine (T-DM1), pertuzumab, afatinib, TAK-285, Neratinib, Dacomitinib, BMS-690514, BMS-599626, Pelitinib, CP-724714, Lapatinib, TAK-165, ARRY-380, AZD8931, or Neratinib.

40. The method of claim 38 , wherein the HER2 kinase activating mutation is chosen from:

(i) a substitution at residue 310 of HER2;

(ii) a substitution of a serine residue at position 310 (S310) of HER2 to phenylalanine;

(iii) a substitution of a serine residue at position 310 (S310) of HER2 to tyrosine;

(iv) a substitution at residue 157 of HER2; or

(v) a substitution of an arginine residue at position 157 (R157) of HER2 to tryptophan.

41. The method of claim 40 , wherein the HER2 kinase activating mutation is a substitution at residue 310 of HER2.

42. The method of claim 41 , wherein the HER2 kinase activating mutation is a substitution of residue 5310 of HER2 to phenylalanine or tyrosine.

43. The method of claim 40 , wherein the HER2 comprises the amino acid sequence of SEQ ID NO: 1.

44. The method of claim 38 , wherein the HER2 comprises the amino acid sequence of SEQ ID NO: 1.

45. The method of claim 38 , wherein the agent that inhibits HER2 is an anti-HER2 antibody molecule, or a conjugate thereof.

46. The method of claim 38 , wherein the subject is a human.

47. The method of claim 38 , wherein the carcinoma is identified as not having an elevated level of a HER2 gene product.

48. The method of claim 47 , wherein the carcinoma is identified as having a micropapillary histology.

49. The method of claim 40 , wherein the HER2 kinase activating mutation is a substitution at residue 157 of HER2.