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Non-mutated kinases in prostate cancer metastasis: drivers and therapeutic targets

  • Author(s): Faltermeier, Claire
  • Advisor(s): Mikkola, Hanna
  • et al.
Abstract

Metastatic prostate cancer lacks effective treatments and is a major cause of death in the United States. Targeting mutationally activated protein kinases has improved patient survival in numerous cancers. However, genetic alterations resulting in constitutive kinase activity are rare in metastatic prostate cancer. Evidence suggests that non-mutated, wild-type kinases are involved in advanced prostate cancer, but it remains unknown whether kinases contribute mechanistically to metastasis and should be pursued as therapeutic targets. Using a mass- spectrometry based phosphoproteomics approach, we identified tyrosine, serine, and threonine kinases that are differentially activated in human metastatic prostate cancer tissue specimens compared to localized disease. To investigate the functional role of these kinases in prostate cancer metastasis, we screened over 100 kinases identified from our phosphoproteomic and previously-published transcriptomic studies for their ability to drive metastasis. In a primary screen using a lung colonization assay, we identified 20 kinases that when overexpressed in murine prostate cancer cells could promote metastasis to the lungs with different latencies. We queried these 20 kinases in a secondary in vivo screen using non-malignant human prostate cells. The kinases MERTK, NTRK2 and RAF family members drove the formation of bone and visceral metastasis confirmed by PET/CT imaging and histology. Immunohistochemistry of tissue microarrays indicated these kinases are highly expressed in human metastatic prostate cancer tissues. Lastly, inhibition studies in metastatic prostate cancer cell lines have revealed that one of the RAF family members, CRAF, may block metastasis. These data demonstrate the strong capability of wild-type protein kinases to drive metastatic colonization and implicate select kinases as potential targets for therapeutic intervention.

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