KIT low Cells Mediate Imatinib Resistance in Gastrointestinal Stromal Tumor

• Published in: Molecular cancer therapeutics 2021-10, Vol.20 (10), p.2035
• Main Authors: Banerjee, Sudeep, Yoon, Hyunho, Ting, Stephanie, Tang, Chih-Min, Yebra, Mayra, Wenzel, Alexander T, Yeerna, Huwate, Mesirov, Jill P, Wechsler-Reya, Robert J, Tamayo, Pablo, Sicklick, Jason K
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - pharmacology; Apoptosis; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; Cell Proliferation; Drug Resistance, Neoplasm; Gastrointestinal Neoplasms - drug therapy; Gastrointestinal Neoplasms - metabolism; Gastrointestinal Neoplasms - pathology; Gastrointestinal Stromal Tumors - drug therapy; Gastrointestinal Stromal Tumors - metabolism; Gastrointestinal Stromal Tumors - pathology; Gene Expression Regulation, Neoplastic - drug effects; Humans; Imatinib Mesylate - pharmacology; Male; Mice; Mice, Nude; Neoplastic Stem Cells - drug effects; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Proto-Oncogene Proteins c-kit - antagonists & inhibitors; Proto-Oncogene Proteins c-kit - genetics; Proto-Oncogene Proteins c-kit - metabolism; Tumor Cells, Cultured; Xenograft Model Antitumor Assays
• ISSN: 1538-8514

Gastrointestinal stromal tumor (GIST) is commonly driven by oncogenic mutations that are effectively targeted by imatinib (IM), a tyrosine kinase inhibitor (TKI). However, IM does not cure GIST, and adjuvant therapy only delays recurrence in high-risk tumors. We hypothesized that GIST contains cells with primary IM resistance that may represent a reservoir for disease persistence. Here, we report a subpopulation of CD34 KIT human GIST cells that have intrinsic IM resistance. These cells possess cancer stem cell-like expression profiles and behavior, including self-renewal and differentiation into CD34 KIT progeny that are sensitive to IM treatment. We also found that TKI treatment of GIST cell lines led to induction of stem cell-associated transcription factors ( and ) and concomitant enrichment of the CD34 KIT cell population. Using a data-driven approach, we constructed a transcriptomic-oncogenic map (Onco-GPS) based on the gene expression of 134 GIST samples to define pathway activation during GIST tumorigenesis. Tumors with low KIT expression had overexpression of cancer stem cell gene signatures consistent with our findings. Additionally, these tumors had activation of the Gas6/AXL pathway and NF-κB signaling gene signatures. We evaluated these targets and found that primary IM-resistant GIST cells were effectively targeted with either single-agent bemcentinib (AXL inhibitor) or bardoxolone (NF-κB inhibitor), as well as with either agent in combination with IM. Collectively, these findings suggest that CD34 KIT cells represent a distinct, but targetable, subpopulation in human GIST that may represent a novel mechanism of primary TKI resistance, as well as a target for overcoming disease persistence following TKI therapy.