Chk1 suppresses a caspase-2 apoptotic response to DNA damage that bypasses p53, bcl-2 and caspase-3
The invention describes methods that are useful for treating cancer by administering a Chk1 inhibitor which can induce apoptosis in p53-defective cells when combined with a chemotherapy and/or radiotherapy. Methods for screening candidates for a Chk1 inhibitor-based cancer treatment regimen are also described.
1. A method for determining whether a subject having a cancer is a candidate for a Chk1 inhibitor-based cancer treatment regimen, comprising:
contacting cancer cells of the subject with a Chk1 inhibitor, in conjunction with a genotoxic stress, and then
determining caspase-2 activation in the cancer cells,
wherein if there is caspase-2 activation in the cancer cells, then the subject is identified as a candidate for a Chk1 inhibitor-based cancer treatment regimen.
2. The method of claim 1 , wherein the cancer cells are contacted with the Chk1 inhibitor, in conjunction with a genotoxic stress, in vivo.
3. The method of claim 2 , wherein caspase-2 activation is determined by
comparing a first level of caspase-2 activity determined in the cancer cells after the cancer cells are contacted with the Chk1 inhibitor, in conjunction with the genotoxic stress to a second level of caspase-2 activity determined in control cells,
wherein if the first level of caspase-2 activity is greater than the second level of caspase-2 activity, then there is caspase-2 activation.
4. The method of claim 3 , wherein the control cells are selected from the group consisting of: Hela cells, Jurkat cells, HCT116 colon carcinoma cells, SAOS2 osteosarcoma, the MDA-MB-435 breast cancer cells, and LN-428 glioblastoma cells.
5. The method of claim 3 , wherein the control cells are a sample of cancer cells obtained from the subject before contacting in vivo the cancer cells with the Chk1 inhibitor in conjunction with a genotoxic stress.
6. The method of claim 2 , wherein the genotoxic stress is a chemotherapy, a radiotherapy or combination thereof.
7. The method of claim 1 , wherein the cancer cells are a first sample of cancer cells obtained from the subject and contacted with the Chk1 inhibitor, in conjunction with a genotoxic stress, ex vivo or in vitro.
8. The method of claim 7 , wherein the caspase-2 activation is determined by:
comparing a first level of caspase-2 activity determined in the first sample of cancer cells after the first sample of cancer cells is contacted with the Chk1 inhibitor, in conjunction with the genotoxic stress to a second level of caspase-2 activity in determined in control cells,
wherein if the first level of caspase-2 activity is greater than the second level of caspase-2 activity, then there is caspase-2 activation.
9. The method of claim 8 , wherein the control cells are selected from the group consisting of: Hela cells, Jurkat cells, HCT116 colon carcinoma cells, SAOS2 osteosarcoma, the MDA-MB-435 breast cancer cells, and LN-428 glioblastoma cells.
10. The method of claim 8 , wherein the control cells are a second sample of cancer cells obtained from the subject and not contacted with the Chk1 inhibitor.