Synergism of FAK and tyrosine kinase inhibition in Ph⁺ B-ALL.

Abstract

BCR-ABL1⁺ B progenitor acute lymphoblastic leukemia (Ph⁺ B-ALL) is an aggressive disease that frequently responds poorly to currently available therapies. Alterations in <i>IKZF1</i>, which encodes the lymphoid transcription factor Ikaros, are present in over 80% of Ph⁺ ALL and are associated with a stem cell-like phenotype, aberrant adhesion molecule expression and signaling, leukemic cell adhesion to the bone marrow stem cell niche, and poor outcome. Here, we show that FAK1 is upregulated in Ph⁺ B-ALL with further overexpression in IKZF1-altered cells and that the FAK inhibitor VS-4718 potently inhibits aberrant FAK signaling and leukemic cell adhesion, potentiating responsiveness to tyrosine kinase inhibitors, inducing cure in vivo. Thus, targeting FAK with VS-4718 is an attractive approach to overcome the deleterious effects of FAK overexpression in Ph⁺ B-ALL, particularly in abrogating the adhesive phenotype induced by Ikaros alterations, and warrants evaluation in clinical trials for Ph⁺ B-ALL, regardless of <i>IKZF1</i> status.