Determinants of sensitivity to chemotherapeutic agents
The present invention provides methods for determining the level of resistance of a tumor cell to one or more chemotherapeutic agents, comprising measuring the level of expression of a muscle ankyrin repeat protein in the tumor cell. The invention also provides methods for increasing the sensitivity of a tumor cell to one or more chemotherapeutic agents, comprising administering to the cell an effective amount of an antagonist of a muscle ankyrin repeat protein. The invention further provides compositions for use in accordance with methods of the invention.
1. A method for increasing sensitivity of a tumor cell to one or more chemotherapeutic agents, the method comprising administering to the tumor cell an effective amount of an antagonist of a muscle ankyrin repeat protein, wherein the antagonist comprises an inhibitor of muscle ankyrin repeat protein expression that is a nucleic acid-based inhibitor.
2. The method of claim 1 wherein the nucleic acid-based inhibitor is an siRNA molecule or an antisense construct.
3. The method of claim 2 wherein the nucleic acid-based inhibitor is an siRNA molecule.
4. The method of claim 1 wherein the muscle ankyrin repeat protein is ANKRD1.
5. The method of claim 3 wherein the siRNA molecule comprises a nucleotide sequence having at least 80% sequence identity to a polynucleotide sequence as set forth in any one of SEQ ID NOs:5, 6 or 7, or a dsRNA corresponding thereto.
6. The method of claim 1 , wherein the chemotherapeutic agent is a platinum-based chemotherapeutic agent.
7. A method for substantially inhibiting expression of a muscle ankyrin repeat protein in tumor cells, comprising introducing into the tumor cells an effective amount of an antagonist of the muscle ankyrin repeat protein wherein the antagonist comprises an inhibitor of muscle ankyrin repeat protein expression that is a nucleic acid-based inhibitor.
8. The method of claim 7 , wherein the muscle ankyrin repeat protein is ANKRD1.
9. A method for substantially inhibiting expression of a muscle ankyrin repeat protein in tumor cells, comprising introducing into the tumor cells an effective amount of an inhibitory nucleic acid construct, said inhibitory nucleic acid construct comprising at least one of (a) a nucleotide sequence specific to at least a portion of a polynucleotide encoding a muscle ankyrin repeat protein, and (b) a nucleotide sequence specific to at least a portion of a regulatory region of a gene encoding the muscle ankyrin repeat protein of (a), wherein the inhibitory nucleic acid construct substantially inhibits expression of the muscle ankyrin repeat protein in tumor cells.
10. A method for increasing sensitivity of tumor cells to one or more chemotherapeutic agents, comprising introducing into the tumor cells an effective amount of an inhibitory nucleic acid construct, said inhibitory nucleic acid construct comprising at least one of (a) a nucleotide sequence specific to at least a portion of a polynucleotide encoding a muscle ankyrin repeat protein, and (b) a nucleotide sequence specific to at least a portion of a regulatory region of a gene encoding the muscle ankyrin repeat protein of (a), wherein the inhibitory nucleic acid construct substantially inhibits expression of the muscle ankyrin repeat protein in tumor cells.
11. The method of claim 6 , wherein the platinum-based chemotherapeutic agent is selected from cisplatin, carboplatin and oxaliplatin.
12. The method of claim 7 wherein the nucleic acid-based inhibitor is an siRNA molecule or an antisense construct.
13. The method of claim 12 wherein the nucleic acid-based inhibitor is an siRNA molecule.
14. The method of claim 13 wherein the siRNA molecule comprises a nucleotide sequence having at least 80% sequence identity to a polynucleotide sequence as set forth in any one of SEQ ID NOs:5, 6 or 7, or a dsRNA corresponding thereto.