Poor prognosis and resistance to
therapy in
malignant gliomas is mainly due to the highly dispersive nature of
glioma cells. This dispersive characteristic results from genetic alterations in key regulators of cell migration and diffusion. A better understanding of these regulatory signals holds promise to improve overall survival and response to
therapy. Using mapping arrays to screen for genomic alterations in
gliomas, we recently identified alterations of the
protein tyrosine phosphatase receptor type kappa gene (PTPRK) that correlate to patient outcomes. These PTPRK alterations are very relevant to
glioma biology as PTPRK can directly sense cell-cell contact and is a dephosphorylation regulator of
tyrosine phosphorylation signaling, which is a major driving force behind
tumor development and progression. Subsequent sequencing of the full length PTPRK transcripts revealed novel PTPRK gene deletion and missense mutations in numerous
glioma biopsies. PTPRK mutations were cloned and expressed in PTPRK-null
malignant glioma cells. The effect of these mutations on PTPRK anti-oncogenic function and their association with response to anti-
glioma therapeutics, such as
temozolomide and
tyrosine kinase inhibitors, was subsequently analyzed using in vitro cell-based assays. These genetic variations altered PTPRK activity and its post-translational processing. Reconstitution of wild-type PTPRK in
malignant glioma cell lines suppressed cell growth and migration by inhibiting EGFR and β-
catenin signaling and improved the effect of conventional
therapies for
glioma. However, PTPRK mutations abrogated
tumor suppressive effects of wild-type PTPRK and altered sensitivity of
glioma cells to
chemotherapy.