Method for Identifying Genes Involved in Trail-Induced Apoptosis and Therapeutic Applications Thereof

A method for sensitizing cells to TRAIL-induced apoptosis, said method comprising the step of contacting said cells with a product capable of sensitizing cells to TRAIL-induced apoptosis, wherein said product is selected from the group comprising:

• inhibitors of the expression of a gene inducing resistance of cells to TRAIL, said gene comprising a nucleotide sequence as shown in SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4 or SEQ ID NO:5 or comprising a nucleotide sequence having at least 70% of identity, particularly at least 80% of identity, more particularly at least 90% identity with a nucleotide sequence selected from the group consisting of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4 and SEQ ID NO:5
• activators of the expression of a gene sensitizing cells to TRAIL-induced apoptosis, said gene comprising a nucleotide sequence as shown in SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15 or SEQ ID NO:16 or comprising a nucleotide sequence having at least 70% of identity, particularly at least 80% of identity, more particularly at least 90% identity with a nucleotide sequence selected from the group consisting of SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15 and SEQ ID NO:16;
• expression vectors comprising a nucleotide sequence as shown in SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15 or SEQ ID NO:16 or comprising a nucleotide sequence having at least 70% of identity, particularly at least 80% of identity, more particularly at least 90% identity with a nucleotide sequence selected from the group consisting of SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15 and SEQ ID NO:16, and
• proteins able to sensitize cells to TRAIL-induced apoptosis, said proteins being encoded by a nucleotide sequence as shown in SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15 or SEQ ID NO:16 or by a nucleotide sequence having at least 70% of identity, particularly at least 80% of identity, more particularly at least 90% identity with a nucleotide sequence selected from the group consisting of SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15 and SEQ ID NO:16.

A method for treating a hyperproliferative disease in a human or animal body, comprising administering to said human or animal an effective amount of a product capable of sensitizing cells to TRAIL-induced apoptosis wherein said product is selected from the group comprising:

• inhibitors of the expression of a gene inducing resistance of cells to TRAIL, said gene comprising a nucleotide sequence as shown in SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4 or SEQ ID NO:5 or comprising a nucleotide sequence having at least 70% of identity, particularly at least 80% of identity, more particularly at least 90% identity with a nucleotide sequence selected from the group consisting of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4 and SEQ ID NO:5
• activators of the expression of a gene sensitizing cells to TRAIL-induced apoptosis, said gene comprising a nucleotide sequence as shown in SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15 or SEQ ID NO:16 or comprising a nucleotide sequence having at least 70% of identity, particularly at least 80% of identity, more particularly at least 90% identity with a nucleotide sequence selected from the group consisting of SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15 and SEQ ID NO:16
• expression vectors comprising a nucleotide sequence as shown in SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15 or SEQ ID NO:16 or comprising a nucleotide sequence having at least 70% of identity, particularly at least 80% of identity, more particularly at least 90% identity with a nucleotide sequence selected from the group consisting of SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15 and SEQ ID NO:16, and
• proteins able to sensitize cells to TRAIL-induced apoptosis, said proteins being encoded by a nucleotide sequence as shown in SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15 or SEQ ID NO:16 or by a nucleotide sequence having at least 70% of identity, particularly at least 80% of identity, more particularly at least 90% identity with a nucleotide sequence selected from the group consisting of SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15 and SEQ ID NO:16.

A method for determining the responsiveness of a subject suffering from a hyperproliferative disease to TRAIL, comprising the step of detecting, in hyperproliferative cells obtained from said subject:

• a) the expression of a gene inducing resistance of said cells to TRAIL-induced apoptosis wherein said gene comprises a nucleotide sequence as shown in SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4 or SEQ ID NO:5 or comprises a nucleotide sequence having at least 70% of identity, particularly at least 80% of identity, more particularly at least 90% identity with a nucleotide sequence selected from the group consisting of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4 and SEQ ID NO:5, and wherein the detection of the expression of a gene inducing resistance of said cells to TRAIL-induced apoptosis indicates that said subject is not responsive to TRAIL,
• and/or
• b) the expression of a gene sensitizing said cells to TRAIL-induced apoptosis wherein said gene comprises a nucleotide sequence as shown in SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15 or SEQ ID NO:16 or comprises a nucleotide sequence having at least 70% of identity, particularly at least 80% of identity, more particularly at least 90% identity with a nucleotide sequence selected from the group consisting of SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15 and SEQ ID NO:16, and wherein the detection of the expression of a gene sensitizing said cells to TRAIL-induced apoptosis indicates that said subject is responsive to TRAIL.

A pharmaceutical composition comprising a product capable of sensitizing cells to TRAIL-induced apoptosis, together with a pharmaceutically acceptable carrier, wherein said product is selected from the group comprising:

• inhibitors of the expression of a gene inducing resistance of cells to TRAIL, said gene comprising a nucleotide sequence as shown in SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4 or SEQ ID NO:5 or comprising a nucleotide sequence having at least 70% of identity, particularly at least 80% of identity, more particularly at least 90% identity with a nucleotide sequence selected from the group consisting of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4 and SEQ ID NO:5
• activators of the expression of a gene sensitizing cells to TRAIL-induced apoptosis, said gene comprising a nucleotide sequence as shown in SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15 or SEQ ID NO:16 or comprising a nucleotide sequence having at least 70% of identity, particularly at least 80% of identity, more particularly at least 90% identity with a nucleotide sequence selected from the group consisting of SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15 and SEQ ID NO:16
• expression vectors comprising a nucleotide sequence as shown in SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15 or SEQ ID NO:16 or comprising a nucleotide sequence having at least 70% of identity, particularly at least 80% of identity, more particularly at least 90% identity with a nucleotide sequence selected from the group consisting of SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15 and SEQ ID NO:16, and
• proteins able to sensitize cells to TRAIL-induced apoptosis, said proteins being encoded by a nucleotide sequence as shown in SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15 or SEQ ID NO:16 or by a nucleotide sequence having at least 70% of identity, particularly at least 80% of identity, more particularly at least 90% identity with a nucleotide sequence selected from the group consisting of SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15 and SEQ ID NO:16.

A method for determining the prognosis of a subject suffering from a hyperproliferative disease, comprising the step of detecting, in a sample obtained from said subject:

• a) the expression of a gene inducing resistance to TRAIL-induced apoptosis wherein said gene comprises a nucleotide sequence as shown in SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4 or SEQ ID NO:5 or comprises a nucleotide sequence having at least 70% of identity, particularly at least 80% of identity, more particularly at least 90% identity with a nucleotide sequence selected from the group consisting of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4 and SEQ ID NO:5, wherein said expression indicates that the subject has a poor prognosis,
• and/or
• b) the expression of a gene sensitizing said cells to TRAIL-induced apoptosis wherein said gene comprises a nucleotide sequence as shown in SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15 or SEQ ID NO:16 or comprises a nucleotide sequence having at least 70% of identity, particularly at least 80% of identity, more particularly at least 90% identity with a nucleotide sequence selected from the group consisting of SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15 and SEQ ID NO:16, wherein said expression indicates that the subject has a good prognosis.

A method for sensitizing cells to TRAIL-induced apoptosis in a human or animal body, said method comprising administering an effective amount of a product selected from the group comprising:

• inhibitors of the expression of a gene inducing resistance of cells to TRAIL, said gene comprising a nucleotide sequence as shown in SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4 or SEQ ID NO:5 or comprising a nucleotide sequence having at least 70% of identity, particularly at least 80% of identity, more particularly at least 90% identity with a nucleotide sequence selected from the group consisting of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4 and SEQ ID NO:5
• activators of the expression of a gene sensitizing cells to TRAIL-induced apoptosis, said gene comprising a nucleotide sequence as shown in SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15 or SEQ ID NO:16 or comprising a nucleotide sequence having at least 70% of identity, particularly at least 80% of identity, more particularly at least 90% identity with a nucleotide sequence selected from the group consisting of SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15 and SEQ ID NO:16,
• expression vectors comprising a nucleotide sequence as shown in SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15 or SEQ ID NO:16 or comprising a nucleotide sequence having at least 70% of identity, particularly at least 80% of identity, more particularly at least 90% identity with a nucleotide sequence selected from the group consisting of SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15 and SEQ ID NO:16, and
• proteins able to sensitize cells to TRAIL-induced apoptosis, said proteins being encoded by a nucleotide sequence as shown in SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15 or SEQ ID NO:16 or by a nucleotide sequence having at least 70% of identity, particularly at least 80% of identity, more particularly at least 90% identity with a nucleotide sequence selected from the group consisting of SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15 and SEQ ID NO:16.