Abstract
Cancer cells depend on actin cytoskeleton rearrangement to carry out hallmark malignant functions including activation, proliferation, migration and invasiveness. Wiskott–Aldrich Syndrome protein (WASp) is an actin nucleation-promoting factor and is a key regulator of actin polymerization in hematopoietic cells. The involvement of WASp in malignancies is incompletely understood. Since WASp is exclusively expressed in hematopoietic cells, we performed in silico screening to identify small molecule compounds (SMCs) that bind WASp and promote its degradation. We describe here one such identified molecule; this WASp-targeting SMC inhibits key WASp-dependent actin processes in several types of hematopoietic malignancies in vitro and in vivo without affecting naïve healthy cells. This small molecule demonstrates limited toxicity and immunogenic effects, and thus, might serve as an effective strategy to treat specific hematopoietic malignancies in a safe and precisely targeted manner.
Highlights
Cancer cells depend on actin cytoskeleton rearrangement to carry out hallmark malignant functions including activation, proliferation, migration and invasiveness
The role of Wiskott–Aldrich Syndrome protein (WASp) in malignant cells is poorly understood in comparison to the well-known properties of its homologs Neural Wiskott–Aldrich Syndrome protein (N-WASp) and WASp family verprolin homologous protein (WAVE) in non-hematopoietic cells
We leveraged the natural mechanism of WASp ubiquitylation and degradation as a strategy to target hematopoietic cancer cells
Summary
Cancer cells depend on actin cytoskeleton rearrangement to carry out hallmark malignant functions including activation, proliferation, migration and invasiveness. We describe here one such identified molecule; this WASptargeting SMC inhibits key WASp-dependent actin processes in several types of hematopoietic malignancies in vitro and in vivo without affecting naïve healthy cells This small molecule demonstrates limited toxicity and immunogenic effects, and might serve as an effective strategy to treat specific hematopoietic malignancies in a safe and precisely targeted manner. Treatments with antiCD19 chimeric antigen receptor-modified T (CAR-T) cells in patients with relapsed acute lymphoblastic leukemia (ALL) or refractory B-cell lymphomas showed limited success[12,13] These new immune-based treatments might help to minimize the severe side effects of chemotherapy and radiotherapy, there are many reports of patients who still develop severe side effects from damage to healthy bystander cells, renal damage, cytokine release syndrome, and graft-versus-host disease (GVHD)[14,15,16]. The development of new drugs to treat hematopoietic malignancies with minimal side effects and higher efficacy is still a critical unmet need
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