CBP/Catenin antagonists: Targeting LSCs' Achilles heel

Abstract

Cancer stem cells (CSCs), including leukemia stem cells (LSCs), exhibit self-renewal capacity and differentiation potential and have the capacity to maintain or renew and propagate a tumor/leukemia. The initial isolation of CSCs/LSCs was in adult myelogenous leukemia, although more recently, the existence of CSCs in a wide variety of other cancers has been reported. CSCs, in general, and LSCs, specifically with respect to this review, are responsible for initiation of disease, therapeutic resistance and ultimately disease relapse. One key focus in cancer research over the past decade has been the development of therapies that safely eliminate the LSC/CSC population. One major obstacle to this goal is the identification of key mechanisms that distinguish LSCs from normal endogenous hematopoietic stem cells. An additional daunting feature that has recently come to light with advances in next-generation sequencing and single-cell sequencing is the heterogeneity within leukemias/tumors, with multiple combinations of mutations, gain and loss of function of genes, and so on being capable of driving disease, even within the CSC/LSC population. The focus of this review/perspective is on our work in identifying and validating, in both chronic myelogenous leukemia and acute lymphoblastic leukemia, a safe and efficacious mechanism to target an evolutionarily conserved signaling nexus, which constitutes a common "Achilles heel" for LSCs/CSCs, using small molecule-specific CBP/catenin antagonists.

Figure 1

(A) An asymmetric division results in the production of two daughter cells with different cell fates – one a stem cell and the other a differentiated transient amplifying (TA) cell. (B) A symmetric proliferative division occurs when the two daughter cells remain as stem cells. A symmetric differentiative division gives rise to two daughter cells, both of which are differentiated TA cells.

Figure 2

(A) Upon translocation into the nucleus, β-catenin can associate with the co-factors CBP upregulating ultimately genes involved in self-renewal, or p300 and thereby genes involved in the initiation of differentiation of the CSC/LSC population. (B) ICG-001 selectively blocks the interaction between β-catenin and CBP. This results in biasing towards p300 usage, and thereby initiates the differentiation transcriptional program with the loss of self-renewal capacity of CSC/LSC. (C) IQ-1, ID8 (both indirectly) and YH 249/250 (directly) block the interaction between β-catenin and p300. By selectively blocking this interaction, CBP usage is increased, and consequently the initiation of a proliferative or self-renewal transcriptional program is favored.

Figure 3

Schematic representation of CBP and p300 and the high percentage of identity at the amino acid level between various regions of these largeKAT3 coactivators.