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Single-Cell Proteomic Profiling Identifies Combined AXL and JAK1 Inhibition as a Novel Therapeutic Strategy for Lung Cancer.
- Source :
-
Cancer research [Cancer Res] 2020 Apr 01; Vol. 80 (7), pp. 1551-1563. Date of Electronic Publication: 2020 Jan 28. - Publication Year :
- 2020
-
Abstract
- 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.<br /> (©2020 American Association for Cancer Research.)
- Subjects :
- Aged
Aged, 80 and over
Animals
Antineoplastic Combined Chemotherapy Protocols therapeutic use
Cell Line, Tumor
Drug Resistance, Neoplasm
Drug Synergism
Epithelial-Mesenchymal Transition drug effects
Feasibility Studies
Female
Flow Cytometry methods
Humans
Janus Kinase 1 metabolism
Lung pathology
Lung Neoplasms pathology
Male
Mice
Middle Aged
Nitriles
Protein Kinase Inhibitors therapeutic use
Proteomics methods
Proto-Oncogene Proteins metabolism
Pyrazoles pharmacology
Pyrazoles therapeutic use
Pyrimidines pharmacology
Pyrimidines therapeutic use
RNA-Seq
Receptor Protein-Tyrosine Kinases metabolism
Signal Transduction drug effects
Single-Cell Analysis methods
Sulfonamides pharmacology
Sulfonamides therapeutic use
Tissue Array Analysis
Xenograft Model Antitumor Assays
Axl Receptor Tyrosine Kinase
Antineoplastic Combined Chemotherapy Protocols pharmacology
Janus Kinase 1 antagonists & inhibitors
Lung Neoplasms drug therapy
Protein Kinase Inhibitors pharmacology
Proto-Oncogene Proteins antagonists & inhibitors
Receptor Protein-Tyrosine Kinases antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1538-7445
- Volume :
- 80
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- Cancer research
- Publication Type :
- Academic Journal
- Accession number :
- 31992541
- Full Text :
- https://doi.org/10.1158/0008-5472.CAN-19-3183