Methods and compositions for increasing susceptibility to radiation treatment by inhibiting suppression of numerical chromosomal instability of cancer cells
Disclosed is a method for increasing susceptibility of cancer cells to ionizing radiation by delivering to the cells a radiosensitizing agent that has one of the following properties: it perturbs the process of chromosome segregation thereby increasing chromosome missegregation; or (b) it is an inhibitor of an agent that promotes faithful chromosome segregation induces numeric chromosome instability in said cells and this instability is induced substantially simultaneously with or closely prior to or closely after irradiating the cells. Examples of such radiosensitizing agent include inhibitors of one or more of the following: Kif2b, MCAK, MPS1, Eg5/Kinesin-5 5, Polo-like kinase 4, MCAK, Bub1 and Hec1. Such agents specifically target proteins involved in maintaining or promoting faithful chromosome segregation.
1. A method for increasing susceptibility of cancer cells to ionizing radiation comprising:
exposing the cancer cells to an effective amount of a radiosensitizing agent, which specifically perturbs the process of chromosome segregation, inducing misaggregation, or specifically inhibits a second agent that promotes faithful chromosome segregation, the radiosensitizing agent thereby inducing numeric chromosome instability in the cells simultaneously with or closely prior to or closely after irradiating the cells with a therapeutically effective dose and regimen of ionizing radiation,
wherein the radiosensitizing agent is selected from the group consisting of Kif2b inhibitors, MCAK inhibitors, Eg5/Kinesin-5 inhibitors, Polo-like kinase 4 inhibitors, NORAD inhibitors, MAD2 inhibitors, and Hec1 inhibitors.
2. The method of claim 1 wherein the radiosensitizing agent specifically inhibits one or more of Kif2b, MCAK, Eg5/Kinesis-5, Polo-like kinase 4, NORAD, MAD2, and Hec1.
3. The method of claim 1 wherein the cancer cells are solid tumor cancer cells.
4. The method of claim 1 wherein the ionizing radiation is administered in two or more divided doses.
5. The method of claim 1 , wherein the radiosensitizing agent is a Kif2b inhibitor.
6. The method of claim 1 , wherein the radiosensitizing agent is a MCAK inhibitor.