Over-expression of the HER family has been implicated in various cancers. Its phosphorylation activates intracellular signaling cascades that regulate proliferation and survival. Although many tyrosine kinase inhibitors (TKI) and antibodies have been developed to target the HER family specifically, resistance to these drugs is still a major issue in cancer treatment. Several recent studies have shown that re-activation of mainly HER3 could play an important role in this resistance. Protein tyrosine phoshatases are enzymes that remove phosphates from phosphorylated tyrosine residues in proteins. Yuan et al. showed that PTPN9 inhibits EGF-evoked signalling by direct dephosphorylation of EGFR and HER2, but the effect on HER3 has not been intensely studied. In this study we identify that PTP9 reduces phosphorylation of HER3 and may therefore be an important player in the development of resistance to targeted therapy. When we inhibited Akt directly using an Akt inhibitor (Akti), we showed a rapid decrease in HER3 phosphorylation as well as an increase in PTPN9. Knocking-out PTPN9 using siRNAs blocked the dephosphorylation of HER3 after Akti treatment, further suggesting the role of PTPN9 in dephosphorylation of HER3. We went on to show that a loss of PTPN9 leads to increased resistance to two commonly used HER-targeting treatments, gefitinib and trastuzumab, in HER2 positive breast cancer cells. Using tumour microarrays with samples from patients with HER2-overexpressing breast cancer we investigated the correlation between levels of PTPN9 and survival. Low levels of PTPN9 correlated with a poor overall survival as well as disease free survival in these patients. Therefore, the preliminary data indicates that PTPN9 could act as a biomarker to predict response to HER-targeted therapy, although the results will need to be verified in a larger sample population. As higher levels of PTPN9 appear to be beneficial to a good clinical response, increasing PTPN9 could also be a new area for drug discovery to focus on.
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