An integrative proteomics approach identifies tyrosine kinase KIT as a therapeutic target for SPINK1-positive prostate cancer
Nishat Manzar,
Umar Khalid Khan,
Ayush Goel,
Shannon Carskadon,
Nilesh Gupta,
Nallasivam Palanisamy,
Bushra Ateeq
Affiliations
Nishat Manzar
Molecular Oncology Laboratory, Department of Biological Sciences and Bioengineering, Indian Institute of Technology Kanpur, Kanpur, UP 208016, India
Umar Khalid Khan
Molecular Oncology Laboratory, Department of Biological Sciences and Bioengineering, Indian Institute of Technology Kanpur, Kanpur, UP 208016, India
Ayush Goel
Molecular Oncology Laboratory, Department of Biological Sciences and Bioengineering, Indian Institute of Technology Kanpur, Kanpur, UP 208016, India
Shannon Carskadon
Vattikuti Urology Institute, Department of Urology, Henry Ford Health System, Detroit, MI 48202, USA
Nilesh Gupta
Department of Pathology, Henry Ford Health System, Detroit, MI 48202, USA
Nallasivam Palanisamy
Vattikuti Urology Institute, Department of Urology, Henry Ford Health System, Detroit, MI 48202, USA
Bushra Ateeq
Molecular Oncology Laboratory, Department of Biological Sciences and Bioengineering, Indian Institute of Technology Kanpur, Kanpur, UP 208016, India; Mehta Family Center for Engineering in Medicine, Indian Institute of Technology Kanpur, Kanpur, UP 208016, India; Centre of Excellence for Cancer - Gangwal School of Medical Sciences and Technology, Indian Institute of Technology Kanpur, Kanpur, UP 208016, India; Corresponding author
Summary: 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.
