A new study published in Molecular Cancer Therapeutics found that CD34+KITlow cells, a subpopulation of gastrointestinal stromal tumor (GIST) cells, may play a role in primary tyrosine kinase inhibitor (TKI) resistance. According to the authors of the study, these cells can be defined as a distinct subpopulation and could be targeted to overcome disease persistence following TKI therapy.
TKIs are used to treat GISTs associated with mutations in the KIT gene. However, these treatments cannot cure the disease, which often persists even after treatment.
Here, a team of researchers led by Jason K. Sicklick MD, FACS, from the Department of Surgery, Division of Surgical Oncology at the University of California in San Diego hypothesized that GISTs may contain a subpopulation of cells that are resistant to imatinib, a TKI commonly used to treat the disease. They thought these cells may represent a reservoir for disease persistence.
Through in vitro experiments, the researchers identified such a subpopulation, called CD34+KITlow. When they analyzed the gene expression profile of these cells, the researchers found that they had cancer stem cell-like expression profiles. They were also able to self-renew and differentiate into CD34+KIThigh cells that are sensitive to imatinib.
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When they treated GIST cells with TKIs, the researchers saw that they started to express stem cell-associated transcription factors such as OCT4 and NANOG. The treatments also led to CD34+KITlow cell population enrichment.
The researchers then “constructed a transcriptomic-oncogenic map based on the gene expression of 134 GIST samples.” Their aim was to define pathway activation during GIST tumorigenesis.
They found that tumors with low KIT expression overexpressed cancer stem cell gene signatures, a finding in accordance with the results of the in vitro experiments. Tumors with low KIT expression also had activation of the Gas6/AXL pathway and NF-κB signaling gene signatures. The researchers decided to treat these tumors with an AXL inhibitor (bemcentinib) and an NF-κB inhibitor (bardoxolone), either on their own or in combination with imatinib. They found that both agents alone or in combination with imatinib effectively targeted primary imatinib-resistant GIST cells.
The authors concluded that CD34+KITlow cells could be targeted to overcome the persistence of GIST following treatment with TKIs.
Banerjee S, Yoon H, Ting S, et al. KIT low cells mediate imatinib resistance in gastrointestinal stromal tumor. Mol Cancer Ther. Published online August 10, 2021. doi:10.1158/1535-7163.MCT-20-0973