Photo by Aaron Logan
Preclinical research suggests that combining a BCL2 inhibitor with a tyrosine kinase inhibitor (TKI) could overcome resistance in Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL).
Investigators found that combining venetoclax and dasatinib increased antitumor activity (when compared to either agent alone) against Ph+ ALL cells in vitro and in a mouse model of the disease.
Jessica Leonard, MD, of Oregon Health & Science University in Portland, and her colleagues reported these findings in Science Translational Medicine.
The researchers said venetoclax and dasatinib demonstrated synergy in vitro, and the combination resulted in a greater degree of apoptosis in Ph+ ALL cells than either agent alone.
The team also observed synergy between venetoclax and cytarabine, dexamethasone, doxorubicin, and vincristine. They said this suggests venetoclax could potentially be used in combination with standard chemotherapy in patients with Ph+ ALL.
The investigators then assessed synergy between venetoclax and other TKIs. Venetoclax demonstrated synergy with imatinib and nilotinib, but the researchers said they saw the most robust synergy when venetoclax was combined with dasatinib or ponatinib.
Further investigation revealed that ponatinib and dasatinib inhibit LYN activity, which impedes STAT5 phosphorylation, which inhibits upregulation of MCL-1.
As upregulation of MCL-1 is a known mechanism of resistance to venetoclax, the researchers believe the addition of either TKI could potentially overcome the development of venetoclax resistance.
Results in a mouse model of Ph+ ALL seemed to support this theory. The researchers injected NSG mice with mononuclear cells from a patient with Ph+ ALL and found that combination treatment with venetoclax and dasatinib prevented engraftment within 90 days in all mice that received the therapy.
In comparison, mice in the control group and those that received single-agent venetoclax engrafted within 60 days. Two of the 5 mice that received dasatinib alone engrafted within 90 days.
In another mouse model, the investigators injected NSG mice with a primary Ph+ ALL sample and found the combination of venetoclax and dasatinib reduced spleen size when compared to no treatment.
In addition, all of the mice that received the combination remained alive during the 4-week treatment period, whereas untreated mice became moribund and were euthanized.
The researchers said these results suggest the combination of dasatinib and venetoclax has the potential to improve the treatment of Ph+ ALL and should be further evaluated for patient care.
