Results of preclinical research indicate that combining 2 kinase inhibitors may be a promising treatment strategy for Philadelphia chromosome-positive B-cell acute lymphoblastic leukemia (Ph+ B-ALL).
Researchers found that combining a tyrosine kinase inhibitor (TKI) and an inhibitor of focal adhesion kinase (FAK) was “remarkably effective” against Ph+ B-ALL in vitro and in vivo.
The TKI dasatinib and the FAK inhibitor VS-4718 decreased leukemic cell survival and adhesion, inhibited tumor growth, and prolonged survival in mouse models of Ph+ B-ALL.
Charles Mullighan, MBBS, MD, of St. Jude Children’s Research Hospital in Memphis, Tennessee, and his colleagues conducted this research and reported their results in JCI Insight.
The researchers noted that patients with Ph+ ALL have shown resistance to TKI therapy, and this resistance has been tied to alterations in IKZF1.
As FAK expression is elevated in IKZF1-mutated leukemias, the team speculated that adding a FAK inhibitor to TKI therapy might lead to better results.
First, the researchers set out to confirm that FAK is overexpressed in Ph+ B-ALL. Their experiments revealed upregulation of the FAK pathway in Ph+ B-ALL cells, with further overexpression of FAK in IKZF1-mutated Ph+ B-ALL cells.
When they inhibited FAK with VS-4718, the team observed decreases in the survival, clonogenicity, and adhesion of IKZF1-mutated Ph+ B-ALL cells from both mice and humans.
Next, the researchers found that VS-4718 synergizes with the TKI dasatinib in vitro and in vivo.
In in vitro experiments with both mouse and human Ph+ B-ALL cells, the combination decreased cell survival and adhesion and inhibited downstream targets of FAK.
In mouse models of Ph+ B-ALL, VS-4718 proved ineffective when given alone.
However, the researchers said the combination of VS-4718 and dasatinib “dramatically” decreased leukemic burden and extended the lives of mice.
In fact, 1 long-term survivor achieved a complete remission that endured after treatment was stopped.
The researchers said these results suggest that targeting FAK with VS-4718 can overcome the deleterious effects of FAK overexpression in Ph+ B-ALL, potentiating responsiveness to TKIs.
