MCL-1 AS A THERAPEUTIC TARGET IN SCFFBW7 DEFICIENT NEOPLASM
Some embodiments are based on the discovery that proliferative diseases (e.g., neoplastic diseases, for example, tumors or cancers) having an FBW7 mutation or other FBW7 deficiency are sensitive to Mc11 inhibiting agents, but resistant to pro-apoptotic drugs that do not inhibit Mc11. Some embodiments provide methods of treating a proliferative disease based on an assessment of FBW7 expression level or mutation status. Some embodiments provide methods of classifying a hyperproliferative cell or cell population, for example, a malignant cell or cell population based on an assessment of FBW7 expression level or mutation status. Some embodiments provide methods of selecting a treatment regimen for treating a proliferative disease, for example, a malignant disorder, based on an assessment of FBW7 expression level or mutation status.
1 - 41 . (canceled)
42 . A method of treating cancer in a subject, the method comprising administering an agent that directly inhibits MCL-1 to a subject having a cancer characterized by a decreased FBW7 expression level or a FBW7 gene comprising a mutation that results in an inability of FBW7 to degrade MCL-1.
43 . The method of claim 42 , wherein the cancer is T-cell acute lymphoblastic leukemia (T-ALL), breast cancer, pancreatic cancer, or colon cancer.
44 . The method of claim 42 , wherein the agent binds directly to MCL-1.
45 . The method of claim 42 , wherein the agent is a small molecule or a peptide.
46 . The method of claim 45 , wherein the peptide is a Mcl-1 BH3 helix Stabilized Alpha-Helix of BCL-2 (SAHB).
47 . The method of claim 45 , wherein the small molecule is obatoclax, apogossypol, or sabutoclax.
48 . The method of claim 42 , wherein the FBW7 gene exhibits a deletion, frameshift mutation, nonsense mutation, or point mutation.
49 . The method of claim 48 , wherein the point mutation is a G423V mutation, a R456C mutation, a R456H mutation, a R479L mutation, a R479Q mutation, a R505C mutation, or a D527G mutation.
50 . A method comprising
(a) determining the expression level and/or the mutation status of the FBW7 gene in a tumor sample obtained from a human subject having a cancer characterized by a decreased FBW7 expression level or a FBW7 gene comprising a mutation that results in an inability of FBW7 to degrade MCL-1; and,
(b) administering an agent that directly inhibits MCL-1 to the subject if the FBW7 expression level is decreased or if the FBW7 gene exhibits a mutation, wherein the mutation causes a loss of function of FBW7, wherein the loss of function of FBW7 results in an inability of FBW7 to degrade MCL-1.
51 . The method of claim 50 , wherein the cancer is T-cell acute lymphoblastic leukemia (T-ALL), breast cancer, pancreatic cancer, or colon cancer.
52 . The method of claim 50 , wherein the agent binds directly to MCL-1.
53 . The method of claim 50 , wherein the agent is a small molecule or a peptide.
54 . The method of claim 53 , wherein the peptide is a Mcl-1 BH3 helix Stabilized Alpha-Helix of BCL-2 (SAHB).
55 . The method of claim 53 , wherein the small molecule is obatoclax, apogossypol, or sabutoclax.
56 . The method of claim 50 , wherein the FBW7 gene exhibits a deletion, frameshift mutation, nonsense mutation, or point mutation.
57 . The method of claim 56 , wherein the point mutation is a G423V mutation, a R456C mutation, a R456H mutation, a R479L mutation, a R479Q mutation, a R505C mutation, or a D527G mutation.