Combining a MEK inhibitor and a BCL-2/BCL-XL inhibitor may be a feasible treatment option for B-cell acute lymphoblastic leukemia (B-ALL), according to preclinical research published in Cell Death and Disease.
Researchers found that, when given alone, the MEK inhibitor trametinib did not block B-ALL cell growth.
And the BCL-2/BCL-XL inhibitors navitoclax (ABT-263) and venetoclax (ABT-199) did not prove particularly effective either.
However, combining trametinib with navitoclax or venetoclax successfully induced apoptosis in B-ALL cells.
“Cancer cells often outwit us by rewiring themselves, but this early research offers a promising idea to get ahead of them,” said study author Richard Marais, PhD, of the Cancer Research UK Manchester Institute.
“We’ll still need to do further research to prove that this is the case beyond cancer cells in the laboratory, and it may take many years before we see it in the clinic, but it’s the first step to finding a new, effective drug combination for B-cell acute lymphoblastic leukemia.”
Dr Marais and his colleagues found that, although the MEK/ERK pathway is activated in B-ALL cells driven by different oncogenes, MEK inhibition alone did not suppress B-ALL cell growth.
And although B-ALL cells were sensitive to treatment with navitoclax or venetoclax alone, the researchers did not see complete loss of cell viability at clinically achievable doses.
However, trametinib did synergize with either navitoclax or venetoclax to suppress proliferation and induce apoptosis in B-ALL cells.
Further investigation revealed that the resistance of B-ALL cells to BCL-2/BCL-XL inhibition is mediated by MCL-1. And the synergism between trametinib and navitoclax/venetoclax is mediated by the pro-apoptotic factor BIM.
BIM is dephosphorylated as a result of MEK inhibition, which allows it to bind to and neutralize MCL-1, thereby enhancing BCL-2/BCL-XL inhibitor-induced cell death.
The researchers said they observed this effect in B-ALL cells driven by a range of genetic abnormalities, so the combination of a MEK inhibitor and a BCL-2/BCL-XL inhibitor could have therapeutic potential in a range of B-ALL subtypes.
