Synergism of FAK and tyrosine kinase inhibition in Ph+B-ALL.
BCR-ABL1+B progenitor acute lymphoblastic leukemia (Ph+B-ALL) is an aggressive disease that frequently responds poorly to currently available therapies. Alterations inIKZF1, 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 ofIKZF1status.
Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Michelle L
ML
Churchman
Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, New South Wales, Sydney, Australia.
Kathryn
K
Evans
Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, New South Wales, Sydney, Australia.
Jennifer
J
Richmond
Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, New South Wales, Sydney, Australia.
Alissa
A
Robbins
Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, New South Wales, Sydney, Australia.
Luke
L
Jones
Verastem Inc., Needham, Massachusetts, USA.
Irina M
IM
Shapiro
Verastem Inc., Needham, Massachusetts, USA.
Jonathan A
JA
Pachter
Verastem Inc., Needham, Massachusetts, USA.
David T
DT
Weaver
Greehey Children's Cancer Research Institute, University of Texas Health Science Center San Antonio, San Antonio, Texas, USA.
Peter J
PJ
Houghton
Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, Maryland, USA.
Malcolm A
MA
Smith
Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, New South Wales, Sydney, Australia.
Richard B
RB
Lock
Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Charles G
CG
Mullighan