Scientists have discovered a small molecule inhibitor that can suppress leukaemic stem cells while also protecting healthy stem cells from toxic chemotherapy in mice.
Leukaemia is an aggressive cancer that is hard to eradicate from the body. Leukaemic stem cells are the drivers of this aggression, with the ability to self-renew and cause disease relapse. Current treatments don’t deplete leukaemic stem cells and are toxic to healthy hematopoietic cells.
“Patients with acute myeloid leukaemia often relapse after suffering severe side effects from chemotherapy, leaving them with very low two-year survival rates,” reported researchers from London’s Francis Crick Institute and collaborators, who conducted the new study.
Published in Science Translational Medicine, the work showed that blocking cyclin-dependent kinase regulatory subunit 1 (CKS1) suppressed leukemic stem cells yet protected healthy stem cells from toxic chemotherapy in mice.
Separating the good from the bad
The researchers first examined leukaemic stem cells and other acute myeloid leukaemia cells taken from patients. They showed that the level of CKS1 was highest in cancerous stem cells.
Next, they used a small-molecule inhibitor of CKS1. The team showed that, in the presence of chemotherapy drugs, it had different effects on cancerous and non-cancerous cells derived from patients. In studies on leukaemia cells, the inhibitor reduced patient-derived blasts and, importantly, depleted leukaemic stem cells. In contrast, the inhibitor protected normal hematopoietic stem cells from chemotherapeutic toxicity.
To delve deeper into the mechanisms of CKS1 inhibition, the researchers used proteomic analysis of cells from a patient-derived xenograft mouse model. This analysis showed that in cancerous cells, inhibition of CKS1 led to hyperactivation of RAC1 (a small GTPase) and caused lethal reactive oxygen species to accumulate in the cells. But this mechanism did not occur in healthy hematopoietic cells. They instead entered quiescence in response to the inhibitor, and so are protected against the effects of chemotherapy.
Targeting vulnerability in stem cell biology
Using the patient-derived xenograft mouse model, the researchers showed that mice receiving doxorubicin and cytarabine along with the CKS1 inhibitor survived longer and had higher amounts of healthy stem cells than mice that received only chemotherapy. Furthermore, the inhibitor spared healthy stem cells grafted into mice and protected cells from the toxic effects of chemotherapy. For example, the inhibitor protected stem cells in the gut, which are often harmed during chemotherapy, leading to gut infections.
Overall, the authors noted that their findings demonstrated that CKS1-dependent proteostasis was a key vulnerability in malignant stem cell biology.
Moreover, some types of solid tumours over-express CKS1B, which opens the possibility that these inhibitors could, in the future, be applied to a broad range of cancers.
The authors suggested, “Similar strategies that exploit this weakness could help reduce relapse rates and improve treatment outcomes in patients.”
This represents a new avenue for therapeutic intervention for patients with acute myeloid leukaemia that merits future clinical study.
Written by Charlotte Harrison, Science Writer
Image Credit: Canva
