PLX134611

GSE105049: Chemoresistant Cancer-Initiating Cell Expansion is Inhibited by Repurposing a Classic Chemotherapeutic Drug as a Targeted Therapy

• Organsim mouse
• Type RNASEQ
• Target gene
• Project ARCHS4

Cancer therapeutic resistance remains a critical, unsolved problem. Residual cancer stem cells (CSCs) may underlie resistance but targeting them remains elusive. Since the Wnt/-catenin and PI3K/Akt pathways cooperatively promote self-renewal and tumorigenesis, and interact through Akt phosphorylation of -catenin at serine552 (pS552--catenin), this interaction may be a driver of therapeutic resistance, which could be targeted. A mouse model with activation of both pathways showed initial expansion of hematopoietic stem/progenitor cells (HSPCs) with subsequent transformation into Lin- c-KitMid CD3+ leukemic stem cells (LSCs), which drive T-cell acute lymphocytic leukemia (T-ALL) development. Unlike bulk, leukemic blast cells, these LSCs are not only chemoresistant but expand in response to chemotherapy and express high levels of pS552--catenin. Unexpectedly, high-throughput screening (HTS) identified doxorubicin (DXR) as an inhibitor of Akt:-catenin interaction even at low doses. We repurposed DXR as a targeted pS552--catenin inhibitor rather than a traditional, broadly cytotoxic chemotherapy. Targeted use of DXR reduced pS552--catenin levels in chemoresistant LSCs, prevented LSC expansion in response to chemotherapy, essentially eliminated LSC tumorigenic activity, and substantially increased survival. Mechanistically, treatment with low-dose DXR targets elements of the -catenin pathway and converts LSCs from a stem cell to a blast cell phenotype. Using patient samples, low-dose DXR treatment inhibits leukemia-initiating activity of human leukemia exhibiting chemoresistant pS552--cat+ LSCs. Our data identify an unexpected and novel target for a classic anti-cancer agent and indicate a more efficacious remedy for overcoming chemoresistance. SOURCE: Shiyuan,(Cynthia),Chen (shc@stowers.org) - Stowers Institute for Medical Research