Combining venetoclax (Venclexta, AbbVie and Genentech) plus a tyrosine kinase inhibitor targeting the BCR-ABL oncogene can eradicate chronic myeloid leukemia stem cells in a mouse model of the disease.
Combining venetoclax (Venclexta, AbbVie and Genentech) plus a tyrosine kinase inhibitor (TKI) targeting the BCR-ABL oncogene can eradicate chronic myeloid leukemia (CML) stem cells in a mouse model of the disease. The results, published in Science Translational Medicine, point to a potential strategy that should be tested in a clinical trial of CML patients and potentially other cancer types with an activated BCR-ABL oncogene.
CML is characterized by a constitutively active BCR-ABL tyrosine kinase as a result of the t(9;22) Philadelphia translocation in hematopoietic stem cells. Targeted oral tyrosine kinase inhibitors that block the activity of BCR-ABL are typically the first line of treatment for CML patients yet these drugs are generally not able to cure CML because they do not target the CML stem cell reservoir. The CML stem cells, which are typically quiescent and nondividing eventually, result in patient recurrence, called blast crisis, due to acquisition of novel BCR-ABL drug resistant mutations.
In the current study, Bing Z. Carter, PhD, and Michael Andreeff, MD, PhD, both of the department of leukemia at the University of Texas MD Anderson Cancer Center and their colleagues, tested the efficacy of a BCR-ABL targeted TKI in combination with venetoclax, a BCL-2 inhibitor in a mouse model of inducible CML.
Venetoclax was approved by the US Food and Drug Administration in April 2016, for the treatment of patients with chronic lymphocytic leukemia (CLL) who have a chromosomal abnormality called 17p deletion and who have been treated with at least one prior therapy. The oral drug is currently also being tested for other hematological malignancies including acute myeloid leukemia (AML), lymphoma, and multiple myeloma.
BCL-2 is a protein that is a negative regulator of apoptosis and has previously been shown to be important for the survival of leukemia stem cells, and venetoclax is thought to work by promoting apoptosis of tumor cells. Prior preclinical data have suggested that combining a BCL-2 inhibitor with a TKI may eliminate CML stem cells.
The study authors demonstrated that the combination of venetoclax plus the BCR-ABL inhibitor nilotinib (Tasigna, Novartis) could inhibit CML stem cells in a transgenic mouse model of CML. Next, the researchers showed that the drug combination specifically resulted in apoptosis of stem blast crisis CML cells derived from six patients who had acquired the T315I BCR-ABL drug resistant mutation and had treatment failure on multiple TKIs. Specifically, the drug combination targeted quiescent CD34+ blast cell CML cells.
“Our results demonstrate that this study in mice employing combined blockade of BCL-2 and BCR-ABL has the potential for curing CML and significantly improving outcomes for patients with blast crisis, and, as such, warrants clinical testing,” said Andreeff in a news release. “This combination strategy may also apply to other malignancies that depend on kinase signaling for progression and maintenance.”