Despite decades of research on AML, the 5-year survival rate of patients with this heterogeneous cancer from diagnosis, through treatment, is just 15% in England.¹ Most drugs used to treat AML cause toxicity to healthy haematopoietic stem cells and fail to prevent future relapse, as they do not target the quiescent leukaemic stem cells (LSCs) that are usually the source of such relapses. Alongside this, older patients are often not eligible for these harsh treatments, leading to a decreased prognosis with age (~5% survival past 5 years for those aged 65 or older compared to >50% for those aged 40 or under).¹ These issues must be overcome to provide patients with AML with a viable treatment option to overcome their disease burden.

 A recent publication by William Grey and colleagues has highlighted a method for specific targeting of LSCs in AML: inhibition of cyclin-dependent kinase regulatory subunit 1 (CKS1).²

Overexpression of the CKS1B gene has previously been associated with poor prognosis in a range of solid tumours, but is an indeterminant factor in AML.^3–5 Researchers were able to show that xenografted mice treated with chemotherapy (doxorubicin and cytarabine), in combination with CKS1 inhibitors (CKS1is), had an increased survival rate compared to those treated with chemotherapy alone.²

Along with showing an improved response to treatment, the researchers also showed that dual treatment with CKS1is and chemotherapy protected healthy stem cells from the toxic effects associated with chemotherapy, and dual-treated mice had a higher number of healthy stem cells than those treated with chemotherapy alone.² 

It is important to note that, while dual therapy protected the healthy stem cells, it still resulted in depletion of LSCs. By pairing CKS1is with traditional chemotherapeutic agents, Grey’s team were able to show increased production of reactive oxygen species, specifically in LSCs; such therapies targeting this population of cells could be critical in overcoming the poor prognosis associated with AML and is an exciting development for the field.²

While this study focussed only on people with AML who were classified as poor risk, having few treatment options and extremely low survival rates (>65 years old, unfavourable cytogenetic profile),² the results seen here hold promise for development of future therapies for people with AML and show the potential power of targeted therapies in treating cancer. Such treatment options could offer a lifeline to patients who are elderly or clinically unfit, where the current side effects associated with chemotherapy would rule them unsuitable for treatment. If inhibition of CKS1 is able to reduce the side effect burden of chemotherapy to a sufficient level, these patients may then be able to meet the selection criteria for other treatments, expanding their treatment options.

References

1. Cancer Research UK. Survival for acute myeloid leukaemia (AML). January 2022. Available at: https://www.cancerresearchuk.org/about-cancer/acute-myeloid-leukaemia-aml/survival (accessed July 2022).
2. Grey W, et al. Sci Transl Med 2022;14(650):eabn3248. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7612983/
3. Salgado R, et al. Genes Chromosomes Cancer 2010;49(11):1054–1061. https://pubmed.ncbi.nlm.nih.gov/20737481/
4. Bock F, et al. Biol Blood Marrow Transplant 2016;22(12):2159–2164. https://pubmed.ncbi.nlm.nih.gov/27638366/
5. Shi L, et al. Oncotarget 2010;1(1):22–33. https://pubmed.ncbi.nlm.nih.gov/20930946/