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 3

VS-4718 inhibits cell-to-stroma adhesion of leukemic murine Arf–/– BCR-ABL1 pre-B cells in the bone marrow niche.

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VS-4718 inhibits cell-to-stroma adhesion of leukemic murine Arf–/– BCR-A...
(A) Calvarial imaging of Arf–/– BCR-ABL1 (Ph) IK6+-GFP leukemic cells in the bone marrow niche, showing stromal adhesion of GFP+ cells in vehicle-treated mice and the nonadhesive “round” phenotype of cells in the bone marrow niche of VS-4718–treated mice. (B) The total number of cells observed per field of view in each calvarium was enumerated to determine whether VS-4718 treatment effects leukemic cell viability or engraftment at this dosage (50 mg/kg). n = 5 fields of view each for 3 calvaria. (C) The phenotype of leukemic cells was categorized by the appearance of “spindle-like” adherent cells or “round” nonadherent appearing cells, indicating loss of adhesion to surrounding stroma due to FAK inhibition with VS-4718. n = 108 cells from vehicle-treated mice and 94 cells from VS-4718–treated mice (3 mice per group, 5 fields of view each). Scale bar: 40 μM.