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
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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

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Figure 2

Focal adhesion kinase inhibition decreases survival, clonogenicity, and adhesion of BCR-ABL1+ B progenitor acute lymphoblastic leukemia cells in vitro.

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Focal adhesion kinase inhibition decreases survival, clonogenicity, and ...
(A) Human BCR-ABL1+ (Ph+) IK6+ h9407 B progenitor acute lymphoblastic leukemia (B-ALL) cells and murine Ph+ pre-B cells expressing empty vector (MIG), IK6+, or the IK1 D186A point mutation have decreased viability when treated with VS-4718 at concentrations above 0.1 μM. (B) Decreased numbers of VS-4718–treated h9407 cells are the result of increased apoptosis. (C) The colony-forming potential of single cell-sorted Ph+ murine pre-B cells of the indicated genotypes is greatly reduced in the presence of VS-4718 at a concentration (0.1 μM) that does not affect cell proliferation or viability. (D) Murine pre-B cells of the indicated genotypes are less adherent to RetroNectin monolayers due to focal adhesion kinase (FAK) inhibition after short-term exposure to VS-4718. (E) Reverse-phase protein array (RPPA) analysis of key FAK pathway targets in human Ph+ IK6+ B-ALL (h9407) cells treated with either vehicle or VS-4718 for 24 hours in vitro. Data represent averages ± SD; n = 3 biological replicates each in A and C, 3 technical replicates in B and D, and 4 technical replicates of 2 biologic replicates in E. *P ≤ 0.05, **P ≤ 0.005, ***P ≤ 0.0005, 2-tailed Student’s t test in B–E with 2-way ANOVA in E. MIG, MSCV-IRES-GFP (empty GFP vector).