Synergism of FAK and tyrosine kinase inhibition in Ph+ B-ALL
Michelle L. Churchman, Kathryn Evans, Jennifer Richmond, Alissa Robbins, Luke Jones, Irina M. Shapiro, Jonathan A. Pachter, David T. Weaver, Peter J. Houghton, Malcolm A. Smith, Richard B. Lock, Charles G. Mullighan
Michelle L. Churchman, Kathryn Evans, Jennifer Richmond, Alissa Robbins, Luke Jones, Irina M. Shapiro, Jonathan A. Pachter, David T. Weaver, Peter J. Houghton, Malcolm A. Smith, Richard B. Lock, Charles G. Mullighan
View: Text | PDF
Research Article Hematology Therapeutics

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 IKZF1, 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 IKZF1 status.

Authors

Michelle L. Churchman, Kathryn Evans, Jennifer Richmond, Alissa Robbins, Luke Jones, Irina M. Shapiro, Jonathan A. Pachter, David T. Weaver, Peter J. Houghton, Malcolm A. Smith, Richard B. Lock, Charles G. Mullighan

×

Figure 1

Focal adhesion kinase pathway upregulation in BCR-ABL1 B progenitor acute lymphoblastic leukemia, with further upregulation by IKZF1 alteration.

Options: View larger image (or click on image) Download as PowerPoint
Focal adhesion kinase pathway upregulation in BCR-ABL1 B progenitor acut...
(A) Gene expression profiling, (B) mRNA sequencing, and (C) protein sequencing of focal adhesion kinase 1 (Fak1) and Fak2 in murine Arf–/– pre-B cells. (D) mRNA sequencing of human BCR-ABL1+ (Ph+) and Ph-like patient cohorts. (E) Reverse-phase protein array (RPPA) analysis of FAK1 expression and downstream targets of FAK signaling in human Ph+ B progenitor acute lymphoblastic leukemia (B-ALL) (h9407) cells with and without IKZF1 alteration (IK6). Data represent averages ± SD; n = 5 technical replicates each in A, 3 (MIG) and 4 (IK6) biological replicates in B, 3 biological replicates in C, 19 Ph+ and 109 Ph-like patients in D, and 4 technical replicates of 2 biological replicates in D. *P ≤ 0.05, **P ≤ 0.005, ***P ≤ 0.0005, 2-tailed Student’s t test. MIG, MSCV-IRES-GFP (empty GFP vector); FPKM, fragments per kilobase of transcripts per million mapped reads.