Single-Cell Proteomic Profiling Identifies Combined AXL and JAK1 Inhibition as a Novel Therapeutic Strategy for Lung Cancer.

Autor:	Taverna JA; Division of Hematology and Oncology, Department of Medicine, University of Texas Health Science Center, San Antonio, Texas., Hung CN; Department of Life Science, Tunghai University, Taichung, Taiwan.; Department of Molecular Medicine, University of Texas Health Science Center, San Antonio, Texas., DeArmond DT; Department of Cardiothoracic Surgery, University of Texas Health Science Center, San Antonio, Texas., Chen M; Department of Molecular Medicine, University of Texas Health Science Center, San Antonio, Texas., Lin CL; Department of Molecular Medicine, University of Texas Health Science Center, San Antonio, Texas., Osmulski PA; Department of Molecular Medicine, University of Texas Health Science Center, San Antonio, Texas., Gaczynska ME; Department of Molecular Medicine, University of Texas Health Science Center, San Antonio, Texas., Wang CM; Department of Molecular Medicine, University of Texas Health Science Center, San Antonio, Texas., Lucio ND; Department of Molecular Medicine, University of Texas Health Science Center, San Antonio, Texas., Chou CW; Department of Molecular Medicine, University of Texas Health Science Center, San Antonio, Texas., Chen CL; Department of Molecular Medicine, University of Texas Health Science Center, San Antonio, Texas., Nazarullah A; Department of Pathology, University of Texas Health Science Center, San Antonio, Texas., Lampkin SR; Department of Pathology, University of Texas Health Science Center, San Antonio, Texas., Qiu L; Department of Pathology, University of Texas Health Science Center, San Antonio, Texas., Bearss DJ; Tolero Pharmaceuticals, Department of Biomarker and Drug Discovery, Lehi, Utah., Warner S; Tolero Pharmaceuticals, Department of Biomarker and Drug Discovery, Lehi, Utah., Whatcott CJ; Tolero Pharmaceuticals, Department of Biomarker and Drug Discovery, Lehi, Utah., Mouritsen L; Tolero Pharmaceuticals, Department of Biomarker and Drug Discovery, Lehi, Utah., Wade M; Tolero Pharmaceuticals, Department of Biomarker and Drug Discovery, Lehi, Utah., Weitman S; Institute for Drug Development, University of Texas Health Science Center, San Antonio, Texas., Mesa RA; Division of Hematology and Oncology, Department of Medicine, University of Texas Health Science Center, San Antonio, Texas., Kirma NB; Department of Molecular Medicine, University of Texas Health Science Center, San Antonio, Texas., Chao WT; Department of Life Science, Tunghai University, Taichung, Taiwan. huangt3@uthscsa.edu wtchao@thu.edu.tw., Huang TH; Department of Molecular Medicine, University of Texas Health Science Center, San Antonio, Texas. huangt3@uthscsa.edu wtchao@thu.edu.tw.
Jazyk:	angličtina
Zdroj:	Cancer research [Cancer Res] 2020 Apr 01; Vol. 80 (7), pp. 1551-1563. Date of Electronic Publication: 2020 Jan 28.
DOI:	10.1158/0008-5472.CAN-19-3183
Abstrakt:	Cytometry by time-of-flight (CyTOF) simultaneously measures multiple cellular proteins at the single-cell level and is used to assess intertumor and intratumor heterogeneity. This approach may be used to investigate the variability of individual tumor responses to treatments. Herein, we stratified lung tumor subpopulations based on AXL signaling as a potential targeting strategy. Integrative transcriptome analyses were used to investigate how TP-0903, an AXL kinase inhibitor, influences redundant oncogenic pathways in metastatic lung cancer cells. CyTOF profiling revealed that AXL inhibition suppressed SMAD4/TGFβ signaling and induced JAK1-STAT3 signaling to compensate for the loss of AXL. Interestingly, high JAK1-STAT3 was associated with increased levels of AXL in treatment-naïve tumors. Tumors with high AXL, TGFβ, and JAK1 signaling concomitantly displayed CD133-mediated cancer stemness and hybrid epithelial-to-mesenchymal transition features in advanced-stage patients, suggesting greater potential for distant dissemination. Diffusion pseudotime analysis revealed cell-fate trajectories among four different categories that were linked to clinicopathologic features for each patient. Patient-derived organoids (PDO) obtained from tumors with high AXL and JAK1 were sensitive to TP-0903 and ruxolitinib (JAK inhibitor) treatments, supporting the CyTOF findings. This study shows that single-cell proteomic profiling of treatment-naïve lung tumors, coupled with ex vivo testing of PDOs, identifies continuous AXL, TGFβ, and JAK1-STAT3 signal activation in select tumors that may be targeted by combined AXL-JAK1 inhibition. SIGNIFICANCE: Single-cell proteomic profiling of clinical samples may facilitate the optimal selection of novel drug targets, interpretation of early-phase clinical trial data, and development of predictive biomarkers valuable for patient stratification. (©2020 American Association for Cancer Research.)
Databáze:	MEDLINE
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