Abstract
Trastuzumab has led to improved survival rates of HER2+ breast cancer patients. However, acquired resistance remains a problem in the majority of cases. t-Darpp is over-expressed in trastuzumab-resistant cell lines and its over-expression is sufficient for conferring the resistance phenotype. Although its mechanism of action is unknown, t-Darpp has been shown to increase cellular proliferation and inhibit apoptosis. We have reported that trastuzumab-resistant BT.HerR cells that over-express endogenous t-Darpp are sensitized to EGFR inhibition in the presence (but not the absence) of trastuzumab. The purpose of the current study was to determine if t-Darpp might modulate sensitivity to EGFR inhibitors in trastuzumab-resistant cells. Using EGFR tyrosine kinase inhibitors AG1478, gefitinib and erlotinib, we found that trastuzumab-resistant SK.HerR cells were sensitized to EGFR inhibition, compared to SK-Br-3 controls, even in the absence of trastuzumab. t-Darpp knock-down in SK.HerR cells reversed their sensitivity to EGFR inhibition. Increased EGFR sensitivity was also noted in SK.tDp cells that stably over-express t-Darpp. High levels of synergy between trastuzumab and the EGFR inhibitors were observed in all cell lines with high t-Darpp expression. These cells also demonstrated more robust activation of EGFR signaling and showed greater EGFR stability than parental cells. The T75A phosphorylation mutant of t-Darpp did not confer sensitivity to EGFR inhibition nor activation of EGFR signaling. The over-expression of t-Darpp might facilitate enhanced EGFR signaling as part of the trastuzumab resistance phenotype. This study suggests that the presence of t-Darpp in HER2+ cancers might predict the enhanced response to dual HER2/EGFR targeting.
Highlights
Breast cancer represents the most common cancer in women worldwide with an estimated 1.6 million new cases diagnosed each year [1, 2]
There was no significant difference in cell proliferation between the parental BT474 and resistant BT.HerR cell lines exposed to AG1478, gefitinib or erlotinib (Fig 1A), consistent with published data showing that enhanced sensitivity to EGFR inhibition in BT.HerR cells requires the presence of trastuzumab
We demonstrate that t-Darpp over-expression sensitizes SK.HerR, but not BT.HerR cells, to EGFR inhibition when trastuzumab itself is not present
Summary
Breast cancer represents the most common cancer in women worldwide with an estimated 1.6 million new cases diagnosed each year [1, 2]. 25–30% of these women present with an over-expression of human epidermal growth factor receptor 2 (HER2) [3]. The amplification of HER2, a receptor tyrosine kinase encoded by the ERBB2 oncogene, correlates with a PLOS ONE | DOI:10.1371/journal.pone.0132267. June 29, 2015 t-Darpp Promotes EGFR Activation analysis, decision to publish, or preparation of the manuscript The amplification of HER2, a receptor tyrosine kinase encoded by the ERBB2 oncogene, correlates with a PLOS ONE | DOI:10.1371/journal.pone.0132267 June 29, 2015 t-Darpp Promotes EGFR Activation analysis, decision to publish, or preparation of the manuscript
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