Enhanced Kat3A/Catenin transcription: a common mechanism of therapeutic resistance

Abstract

Cancers are heterogeneous at the cellular level. Cancer stem cells/tumor initiating cells (CSC/TIC) both initiate tumorigenesis and are responsible for therapeutic resistance and disease relapse. Elimination of CSC/TIC should therefore be able to reverse therapy resistance. In principle, this could be accomplished by either targeting cancer stem cell surface markers or "stemness" pathways. Although the successful therapeutic elimination of "cancer stemness" is a critical goal, it is complex in that it should be achieved without depletion of or increases in somatic mutations in normal tissue stem cell populations. In this perspective, we will discuss the prospects for this goal via pharmacologically targeting differential Kat3 coactivator/Catenin usage, a fundamental transcriptional control mechanism in stem cell biology.

Stromal-induced epithelial-mesenchymal transition induces targetable drug resistance in acute lymphoblastic leukemia

“… 58 , 59 Therefore, we explored if WNT/β-catenin target genes associated with stemness and self-renewal were enriched in Adh ALL cells. 60 Expression of FN1, SNAI2, HAS2, DCLK1, DDND1, CD44, CLDN1, DKK1 , and TERT was enriched in all five Adh cell lines ( Figure S7A ), and expression of genes with promoter TCF4 binding sites was also enriched in Adh ALL cell lines ( Figure S7B ). PRI-724, a selective inhibitor of β-catenin-CBP interaction, reduced the β-catenin-mediated transcriptional activity of NALM6 co-cultured with MSCs at nanomolar range (IC 50 = 172 nM; Figure 7A ), and in contrast to DEX, it inhibited the viability of NALM6 cells co-cultured with MSCs as a single agent ( Figure 7B ).…”