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Updated: Jul 2, 2025
Assessment of Resistance to Tyrosine Kinase Inhibitors by an Interrogation of Signal Transduction Pathways by Antibody Arrays
Published on: September 19, 2018
An integrative proteomics approach identifies tyrosine kinase KIT as a therapeutic target for SPINK1-positive
Nishat Manzar1, Umar Khalid Khan1, Ayush Goel1
1Molecular Oncology Laboratory, Department of Biological Sciences and Bioengineering, Indian Institute of Technology Kanpur, Kanpur, UP 208016, India.
Abstract:
Elevated serine peptidase inhibitor, Kazal type 1 (SPINK1) levels in ∼10%-25% of prostate cancer (PCa) patients associate with aggressive phenotype, for which there are limited treatment choices and dismal clinical outcomes. Using an integrative proteomics approach involving label-free phosphoproteome and proteome profiling, we delineated the downstream signaling pathways involved in SPINK1-mediated tumorigenesis and identified tyrosine kinase KIT as highly enriched. Furthermore, high to moderate levels of KIT expression were detected in ∼85% of SPINK1-positive PCa specimens. We show KIT signaling orchestrates SPINK1-mediated oncogenesis, and treatment with KIT inhibitor reduces tumor growth and metastases in preclinical mice models. Mechanistically, KIT signaling modulates WNT/β-catenin pathway and confers stemness-related features in PCa. Notably, inhibiting KIT signaling led to restoration of AR/REST levels, forming a feedback loop enabling SPINK1 repression. Overall, we uncover the role of KIT signaling downstream of SPINK1 in maintaining lineage plasticity and provide distinct treatment modalities for advanced-stage SPINK1-positive patients.
Insights
Elevated serine peptidase inhibitor, Kazal type 1 (SPINK1) in prostate cancer drives aggressive disease. Targeting tyrosine kinase KIT shows promise in preclinical models, offering new hope for advanced prostate cancer treatment.
Area of Science:
- Oncology
- Molecular Biology
- Proteomics
Background:
- Elevated serine peptidase inhibitor, Kazal type 1 (SPINK1) is found in 10-25% of prostate cancer (PCa) patients, correlating with aggressive phenotypes and poor outcomes.
- Limited treatment options exist for SPINK1-positive aggressive PCa.
Purpose of the Study:
- To delineate downstream signaling pathways in SPINK1-mediated PCa tumorigenesis.
- To identify therapeutic targets for SPINK1-positive PCa.
Main Methods:
- Integrative proteomics: label-free phosphoproteome and proteome profiling.
- Analysis of KIT expression in SPINK1-positive PCa specimens.
- Preclinical mouse models to evaluate KIT inhibitor efficacy.
Main Results:
- Tyrosine kinase KIT was identified as highly enriched in SPINK1-mediated pathways.
- KIT expression was detected in ~85% of SPINK1-positive PCa specimens.
- KIT inhibition reduced tumor growth and metastases in preclinical models, modulated WNT/β-catenin, conferred stemness, and restored AR/REST levels, creating a feedback loop for SPINK1 repression.
Conclusions:
- KIT signaling is a key downstream mediator of SPINK1 oncogenesis in PCa.
- Targeting KIT offers a novel therapeutic strategy for advanced-stage SPINK1-positive PCa patients.
- This study reveals KIT's role in maintaining lineage plasticity and provides potential treatment modalities.
