Abstract
Protein tyrosine kinase 6 (PTK6, or BRK) is aberrantly expressed in breast cancers, and emerging as an oncogene that promotes tumor cell proliferation, migration and evasion. Both kinase-dependent and -independent functions of PTK6 in driving tumor growth have been described, therefore targeting PTK6 kinase activity by small molecule inhibitors as a therapeutic approach to treat cancers remains to be validated. In this study, we identified novel, potent and selective PTK6 kinase inhibitors as a means to investigate the role of PTK6 kinase activity in breast tumorigenesis. We report here the crystal structures of apo-PTK6 and inhibitor-bound PTK6 complexes, providing the structural basis for small molecule interaction with PTK6. The kinase inhibitors moderately suppress tumor cell growth in 2D and 3D cell cultures. However, the tumor cell growth inhibition shows neither correlation with the PTK6 kinase activity inhibition, nor the total or activated PTK6 protein levels in tumor cells, suggesting that the tumor cell growth is independent of PTK6 kinase activity. Furthermore, in engineered breast tumor cells overexpressing PTK6, the inhibition of PTK6 kinase activity does not parallel the inhibition of tumor cell growth with a >500-fold shift in compound potencies (IC50 values). Overall, these findings suggest that the kinase activity of PTK6 does not play a significant role in tumorigenesis, thus providing important evidence against PTK6 kinase as a potential therapeutic target for breast cancer treatment.
Highlights
Non-receptor protein tyrosine kinase 6 (PTK6, or BRK) is expressed in normal epithelia in the gastrointestinal tract and oral cavity, and regulates cell proliferation and differentiation [1,2,3,4,5]
The inhibition of tumor cell growth by PTK6 kinase inhibitors is independent of PTK6 expression or activation levels in cells, and bears no correlation with the inhibition of PTK6 kinase activity, implying that the observed inhibition of tumor cell growth is not driven by PTK6 kinase inhibition, but rather an off-target effect. These results suggest that PTK6 kinase activity does not play an oncogenic function in human breast cancers
PF-6737007, a close structural analogue of PF-6683324 and PF-6689840, was identified as a negative control compound with little activity against PTK6 (IC50 >10 uM). Both Type I
Summary
Non-receptor protein tyrosine kinase 6 (PTK6, or BRK) is expressed in normal epithelia in the gastrointestinal tract and oral cavity, and regulates cell proliferation and differentiation [1,2,3,4,5]. Aberrant expression of PTK6 is frequently detected in epithelial cancers including breast, ovarian, prostate and colon cancers and linked to tumor formation [3, 6,7,8,9,10]. The association of PTK6 with cancers is widely studied in breast cancers. High transcriptional levels of PTK6 are associated with poor disease prognosis in breast cancers [10,11,12,13,14].
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