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 6

Addition of VS-4718 to dasatinib therapy regimen decreases the leukemic burden of xenografted human BCR-ABL1 B progenitor acute lymphoblastic leukemia in vivo and improves survival.

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Addition of VS-4718 to dasatinib therapy regimen decreases the leukemic ...
(A) Live whole-animal quantification of in vivo luciferase activity to monitor the progression of luciferase-tagged h9407 B progenitor acute lymphoblastic leukemia cells during treatment with vehicle compared with VS-4718 as a single agent or (B) dasatinib in combination with VS-4718 versus dasatinib as a single agent. (C) The percentage of human CD45+ (hCD45+) ALL-4 cells in peripheral blood (PB) was determined by flow cytometric analysis to track progression of leukemic cells while on treatment. (D) Kaplan-Meier survival curve of mice in C. (E) Enumeration of hCD45+ ALL-4 cells from PB, cardiac puncture, spleen, and bone marrow at the time of sacrifice of mice in C and D. A sentinel cohort of dasatinib- and VS-4718–treated mice were sacrificed at the end of treatment on day 28 to confirm remission. (F) Western blot analysis of spleen samples from mice on in vivo ALL-4 xenograft treatment, showing inhibition of phosphorylation of FAK at residue Y397 (pFAK-Y397). (G) Quantification of pFAK-Y397 levels by ELISA with OD levels normalized to total protein. Data represent averages ± SD in A–C; n = 9–11 mice in A–D and n = 4 mice in E–G; **P ≤ 0.005, ***P ≤ 0.0005, Mantel-Cox test. Das, dasatinib.