Methods of characterizing resistance to modulators of Cereblon
In one aspect, the present invention features method of identifying a cell resistant to a modulator of Cereblon (CRBN). In another aspect, the present invention features a method of characterizing sensitivity of a subject to a modulator of CRBN. In yet another aspect, the present invention features a method of monitoring sensitivity of a subject to a modulator of CRBN.
1. A method comprising:
(a) detecting loss of function of cereblon (CRBN) and ubiquitin conjugating enzyme E2 (UBE2G1) in B cells or cells derived from B cells in a sample obtained from a human subject having a disease or disorder selected from a plasma cell malignancy, a mature B-cell malignancy, a B-cell neoplasia, multiple myeloma, erythema nodosum leparum, or a myelodysplastic syndrome, by immunoassay, sequencing, or probe hybridization;
(b) stratifying the human subject having loss of function of CRBN and UBE2G1 in the subject's B cells or cells derived from B cells into a patient population that is resistant to lenalidomide or an analog thereof based on detecting the loss of function of CRBN and UBE2G1 in said cells of the subject's sample; and
(c) administering to the human subject a drug that is not lenalidomide or an analog thereof for treating the plasma cell malignancy, mature B-cell malignancy, B-cell neoplasia, multiple myeloma, erythema nodosum leparum, or myelodysplastic syndrome.
2. The method of claim 1 , wherein the subject has a plasma cell malignancy, multiple myeloma, or a myelodysplastic syndrome.
3. The method of claim 1 , further comprising detecting loss of function of COPS2 in the subject's B cells or cells derived from B cells.
4. The method of claim 1 , wherein the analog of lenalidomide is thalidomide or pomalidomide.
5. The method of claim 1 , further comprising detecting loss of function of ubiquitin conjugating enzyme UBE2D3 in the subject's B cells or cells derived from B cells.
6. The method of claim 1 , further comprising detecting loss of function of ubiquitin conjugating enzyme UBE2M in the subject's B cells or cells derived from B cells.
7. A method comprising:
(a) detecting loss of function of cereblon (CRBN) and ubiquitin conjugating enzyme E2 (UBE2G1) in B cells or cells derived from B cells in a biological sample obtained from a human subject having, at risk of having, or susceptible to having a disease or disorder selected from a plasma cell malignancy, a mature B-cell malignancy, a B-cell neoplasia, multiple myeloma, erythema nodosum leparum, or a myelodysplastic syndrome by immunoassay, sequencing, or probe hybridization;
(b) identifying the subject having loss of function of CRBN and UBE2G1 in the subject's B cells or cells derived from B cells as being resistant to lenalidomide or an analog thereof based on said detecting step (a); and
(c) administering to the identified subject a drug that is not lenalidomide or an analog thereof for treating or preventing the disease or disorder selected from plasma cell malignancy, mature B-cell malignancy, B-cell neoplasia, multiple myeloma, erythema nodosum leparum, or myelodysplastic syndrome.
8. The method of claim 7 , wherein the subject has, is at risk of having, or is susceptible to having a plasma cell malignancy, multiple myeloma, or a myelodysplastic syndrome.
9. The method of claim 7 , wherein the analog of lenalidomide is thalidomide or pomalidomide.
10. The method of claim 7 , further comprising detecting loss of function of COPS2 in the subject's B cells or cells derived from B cells.
11. The method of claim 7 , further comprising detecting loss of function of ubiquitin conjugating enzyme UBE2D3 in the subject's B cells or cells derived from B cells.
12. The method of claim 7 , further comprising detecting loss of function of ubiquitin conjugating enzyme UBE2M in the subject's B cells or cells derived from B cells.
13. A method comprising:
(a) detecting loss of function of cereblon (CRBN) and ubiquitin conjugating enzyme E2 (UBE2G1) in B cells or cells derived from B cells in a sample obtained from a human subject having a disease or disorder selected from a plasma cell malignancy, a mature B-cell malignancy, a B-cell neoplasia, multiple myeloma, erythema nodosum leparum, or a myelodysplastic syndrome, by immunoassay, sequencing, or probe hybridization; and
(b) administering to the human subject a drug that is not lenalidomide or an analog thereof for treating the plasma cell malignancy, mature B-cell malignancy, B-cell neoplasia, multiple myeloma, erythema nodosum leparum, or myelodysplastic syndrome in the human subject.
14. The method of claim 13 , wherein the analog of lenalidomide is thalidomide or pomalidomide.
15. The method of claim 13 , further comprising detecting loss of function of COPS2, UBE2D3, or UBE2M in the subject's B cells or cells derived from B cells.