Analysis of “Small Molecules Co-targeting CKIa and the Transcriptional Kinases CDK7/9 Control AML in Preclinical Models”

Ramsey Ritter

The study covered in “Small Molecules Co-targeting CKIa and the Transcriptional Kinases CDK7/9 Control AML in Preclinical Models” is very interesting because it shows a potential way to target cancer cells while leaving healthy cells intact. The drugs developed in this study could help to replace treatments such as chemotherapy, which kill heathy and cancerous cells indiscriminately. This purpose of this research study was to develop CK1a inhibitors in order to phosphorylate p53 and beta-catenin, enabling apoptosis of leukemia cells, using a mouse model. Apoptosis is the programmed, or regulated, death of a cell and enables multicellular organisms to control the number of cells they have, the size of tissues, and protects from damaged cells that imbalance homeostasis (Hengartner, 2000). P53 is a protein that detects damage in cellular DNA and once detected stops proliferation of the cell until the damage is repaired, however, if the DNA cannot be repaired it moves the cell to apoptosis (Johnson, 2013). Phosphorylation of p53 stabilizes the protein and allows it to signal Bax production, leading to apoptosis (Johnson, 2013). Phosphorylation of beta-catenin prevents it from transcribing DNA and allows degradation of the cell to proceed (Donmez, Demirezen and Beksac, 2016).

First, the researcher developed the small molecule CKI inhibitors using medical chemistry (Minzel et al., 2018). They then used KINOMEscan to determine the binding affinity of the drugs (Minzel et al., 2018). The drugs were then tested on mice with different forms of leukemia and mice were monitored post treatment, in order to access their effectiveness (Minzel et al., 2018). The drugs were also introduced to human tissue to determine effectiveness pre-human trials (Minzel et al., 2018). The safety of the drugs was assessed using rats and dogs, with tissues analysis post treatment (Minzel et al., 2018).

Of the drugs tested, those that performed best were A51 and A86. This is surprising because neither is the strongest binder. These drugs target Ck7 and Ck9, which does not allow transcription to occur, stopping the proliferation of the cancer cells (Minzel et al., 2018). Both drugs show an increase in the presence of beta-catenin, and p53. This indicates the inhibitors are creating the desired effect. A51 appears to be more dose dependent regarding p53 presence, with a higher concentration required to elicit the same response of a lower dose of A86. Both drugs only showed higher levels of beta-catenin than the control at higher doses. A86 showed a higher rate of aptosis, using annexin V as an indicator. The spleen and bone marrow of mice treated with A51 look much healthier than those of the control mice, with the spleen reduced to a more normal size and the bone marrow a healthier, red color. At 160 days after inoculation around 50% of mice treated with A51 survived with 0% surviving from the control group. The number of cancer cells was also dramatically lower for days after treatment compared to the control group. When treated bone marrow from sick mice was transplanted into healthy mice the survival rate was 100% for 20 weeks post treatment, with the control group receiving a bone marrow transplant from sick mice having a mortality rate of 100% in 5 weeks. This shows potential for long term therapeutic effects when treating with a bone marrow transplant containing A51.

The results of the study support the hypothesis of the researchers, that CKI inhibitors can be used to potentially cure leukemia. The inhibitors both do and do not cure leukemia. They do not cure it on their own because cancer cells were seen after treating with inhibitors alone. When used in conjunction with radiation to kill the patient’s bone marrow and a bone marrow transplant treated with A51 they do show a cure. These drugs should be used in human trials because the potential to cure leukemia is too great to ignore. The drugs only targeted the cancer cells, leaving healthy tissues intact. This is important because one of the greatest risks to treating cancer is the potential for treatments to cause more harm than good. Treatments such as chemotherapy destroy everything, leaving the patient vulnerable to other disease and disrupt homeostasis. If these drugs can destroy cancer cells with little risk of toxicity or adverse effects there is no reason not to have human trials.

References

Donmez, H., Demirezen, S. and Beksac, M. (2016). The relationship between beta-catenin and apoptosis: A cytological and immunocytochemical examination. Tissue and Cell, 48(3), pp.160-167.

Hengartner, M. (2000). The biochemistry of apoptosis. Nature, 407(6805), pp.770-776.

Johnson, D. (2013). Cell Death Signaling in Cancer Biology and Treatment. New York, NY: Springer, Imprint: Humana Press.

Minzel, W., Venkatachalam, A., Fink, A., Hung, E., Brachya, G., Burstain, I., Shaham, M., Rivlin, A., Omer, I., Zinger, A., Elias, S., Winter, E., Erdman, P., Sullivan, R., Fung, L., Mercurio, F., Li, D., Vacca, J., Kaushansky, N., Shlush, L., Oren, M., Levine, R., Pikarsky, E., Snir-Alkalay, I. and Ben-Neriah, Y. (2018). Small Molecules Co-targeting CKIα and the Transcriptional Kinases CDK7/9 Control AML in Preclinical Models. Cell, 175(1), pp.171-185.e25