KIT as a novel therapeutic target for prostate cancer

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Prostate cancer develops when normal cells become abnormal and grow abruptly in the prostate gland. Although not all abnormal growths are cancerous (malignant), some may be benign and do not spread to other body parts. Prostate cancer stands as the most diagnosed malignancy among men globally. At the molecular level, prostate cancer is a heterogeneous disease, with distinct genomic alterations driving its progression. Our research was focused on a specific molecular subtype called SPINK1-positive prostate cancer, characterized by elevated SPINK1 levels, known for its aggressivity and poor response to standard therapies. To address this challenge, I aimed to identify alternative treatment approaches for SPINK1-positive prostate cancer. We employed advanced proteomic tools to explore the active signaling pathways in SPINK1-positive cancer and found that KIT tyrosine kinase signaling was notably active. We corroborated these findings in clinical specimens obtained from prostate cancer patients and confirmed a positive association between SPINK1 and KIT levels. 

Recognizing the potential of targeting KIT signaling, a pathway implicated in various cancer types and “druggable” using FDA-approved drugs, we investigated the effects of Pexidartinib, a KIT inhibitor, on SPINK1-positive prostate cancer. Interestingly, SPINK1-positive prostate cancer cells treated with this inhibitor showed a remarkable reduction in SPINK1-associated oncogenic characteristics, such as cancer cell proliferation and stemness. In addition, the inhibition of KIT signaling resulted in cellular reprogramming, as marked by the decrease in the expression of markers related to the WNT pathway. Expanding our study beyond cell-based experiments, we investigated the impact of administering KIT inhibitors in the immunodeficient mice bearing SPINK1-positive tumors. The outcomes were noteworthy, revealing a substantial decrease in tumor growth and metastases compared to the control group. Moreover, the KIT inhibitor-treated group showed a striking difference in bone density and other bone morphometric parameters, highlighting the role of KIT signaling in bone lesions. Altogether, our study provides compelling evidence supporting the therapeutic targeting of the KIT tyrosine kinase receptor in advanced-stage prostate cancer, especially in cases with bone metastases.