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 4

VS-4718 synergizes with dasatinib to decrease cell survival and adhesion of BCR-ABL1 B progenitor acute lymphoblastic leukemia cells.

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VS-4718 synergizes with dasatinib to decrease cell survival and adhesion...
(A) VS-4718 synergizes with dasatinib to lower the IC50 of Arf–/– BCR-ABL1 (Ph) pre-B cells expressing MIG or IK6 in cell viability assays. (B) Combination index (CI) values from viability assays shown in A indicate synergistic to additive effects of VS-4718 and dasatinib on MIG cells and strong synergy for IK6 cells (CI ≤ 0.3 = strong synergy; 0.3 < CI ≤ 0.85 = synergy; 0.85 < CI ≤ 1.2 = additive; 1.2 < CI ≤ 3.3 = antagonism; CI > 3.3 = strong antagonism). (C) Cell viability assays with human ALL-4 and ALL-56 cells displayed synergism between VS-4718 and dasatinib; however, the survival of ALL-55 cells was not decreased with combination treatment. (D) Human h9407 B progenitor acute lymphoblastic leukemia cells are less sensitive to increasing concentrations of dasatinib alone compared with combination treatment with VS-4718 in cell viability assays ex vivo. (E) Adhesion assays were used to detect the effects of VS-4718 and dasatinib on the ability of Arf–/– Ph pre-B cells expressing MIG or IK6 to adhere to RetroNectin monolayers in vitro. Combination treatment with VS-4718 and dasatinib synergistically abolished cellular adhesion to RetroNectin. (F) Downstream FAK signaling is inhibited synergistically by VS-4718 and dasatinib in the adherent fraction of cells from the RetroNectin assays shown in E, as detected by Western blotting for p-P130Cas expression at 15 minutes, 30 minutes, and 2 hours of exposure to drug. Data represent averages ± SD of 3 technical replicates for each group in A–E; *P ≤ 0.05, **P ≤ 0.005, ***P ≤ 0.0005, 2-tailed Student’s t test. MIG, MSCV-IRES-GFP (empty GFP vector); Das, dasatinib.