Targeting SUMOylation dependency in human cancer stem cells through a unique SAE2 motif revealed by chemical genomics

Emerging role of G9a in cancer stemness and promises as a therapeutic target

“…A notable example of PDS that led to the identification of a context-specific, CSC-targeting compound was reported by Sachlos et al, using a transformed variant of human ES cells (t-hESCs) as a surrogate model of neoplastic stemness [ 114 ]. With respect to shared transcriptional and epigenetic networks between early development and neoplastic stemness, t-hESCs are well-documented as being predictive of drug responses in human CSCs from different origins [ 6 , 21 , 115 , 116 ]. By monitoring fluctuations in OCT4 promoter activity in t-hESCs following treatments with clinically approved compounds, the authors identified thioridazine, an antipsychotic drug that primarily antagonizes the dopamine receptor D2 (DRD2), as a novel leukemic stem cell targeting agent in vitro and in vivo [ 114 ].…”

“…DRD2 was identified as a new context-specific target in self-renewing leukemic progenitors and represents an attractive therapeutic network to eliminate CSCs without impacting normal hematopoietic stem cells [ 117 ]. Another instance of context-specific pathway and drug candidate identification in CSCs using PDS on t-hESCs was recently reported using natural product extracts from microorganisms [ 6 ]. In this case, a high-throughput screen measuring cell count variations in t-hESCs, and healthy ES cells identified McM025044 as a new SUMOylation inhibitor showing selective toxicity in primary AML CSCs vs. normal hematopoietic progenitors [ 6 ].…”

“…Another instance of context-specific pathway and drug candidate identification in CSCs using PDS on t-hESCs was recently reported using natural product extracts from microorganisms [ 6 ]. In this case, a high-throughput screen measuring cell count variations in t-hESCs, and healthy ES cells identified McM025044 as a new SUMOylation inhibitor showing selective toxicity in primary AML CSCs vs. normal hematopoietic progenitors [ 6 ]. This reinforces the relevance of pathological networks shared between CSCs from somatic cancers and t-hESCs in drug discovery projects, as the SUMOylation pathway was previously documented to be hyperactivated in both, t-hESCs and CSCs from different origins [ 115 , 118 ].…”

“…This reinforces the relevance of pathological networks shared between CSCs from somatic cancers and t-hESCs in drug discovery projects, as the SUMOylation pathway was previously documented to be hyperactivated in both, t-hESCs and CSCs from different origins [ 115 , 118 ]. Interestingly, the cancer-selective inhibition displayed by McM025044 was not observed for other SUMOylation inhibitors such as ML-792, identified via target-centric drug discovery [ 6 ]. It is likely that the PDS pipeline used to screen microorganism extracts, which included a cancer-selective filter where only compounds having a significantly higher impact on the viability of t-hESCs over healthy ES cells, led to the exclusion of non-CSC-selective SUMOylation inhibitor candidates.…”

“…1 ). Key defining characteristics of CSCs, such as self-renewal functions and a tumor-initiating capacity have been extensively documented through in vivo serial transplantation assays, providing robust measures of both properties in limited fractions of bulk tumor mass [ 2 , 5 , 6 ]. More recently, lineage-tracing experiments and barcode sequencing have further increased our knowledge of CSC plasticity and clonal diversity [ 7 – 9 ].…”