Abstract P3-04-13: Protein tyrosine kinase 6 (PTK6) promotes survival of endocrine therapy-resistant ER+ breast cancer cells

Abstract

Abstract Background/Rationale: The non-receptor tyrosine kinase PTK6/Brk is highly expressed in the ER+/Luminal breast cancer subtypes. PTK6 expression has prognostic significance for patients with ER+ disease; higher transcript levels are associated with poorer survival. The functions of PTK6 in the context of ER+ breast cancer and sensitivity to endocrine therapy have not been explored. We sought to determine the functional roles of PTK6 in ER+ breast cancer cells, including those that are relatively resistant to current endocrine therapies. Methods/Results. We modulated the expression of PTK6 using both gain- and loss-of-function approaches. Enhanced expression of PTK6 in Tamoxifen-sensitive ER+ breast cancer cells was sufficient to confer relative Tamoxifen resistance. Furthermore, downregulation of PTK6 in ER+ breast cancer cells, including those that have acquired resistance to Tamoxifen, induced apoptosis, as evidenced by an increase in AnnexinV+ cells and increased levels of cleaved PARP. PTK6 downregulation impaired growth of Tamoxifen-resistant variants of ER+ MCF7 and T47D cells (MCF7TamR and T47DTamR) in 3D Matrigel culture, and virtually abrogated primary tumor growth of MCF7TamR xenografts. Mechanistically, p38MAPK activation is critical for PTK6 downregulation-induced apoptosis of ER+ breast cancer cells, as p38 inhibition partially rescues cells from PTK6 shRNA-associated apoptosis. Conclusions: Our studies highlight the critical role that PTK6 plays in the survival of ER+ breast cancer cells, including those that are resistant to endocrine therapy. Enhanced PTK6 expression in ER+ breast cancer cells is sufficient to promote endocrine therapy resistance, which could contribute to the poorer prognosis associated with higher PTK6 expression in ER+ patient tumors. As small molecule PTK6 inhibitors are becoming available, our studies support further evaluation of PTK6 as a candidate therapeutic target for endocrine therapy resistant ER+ breast cancers. Citation Format: Irie HY, Park SH, Katsyv I, Zhang W, Nayak A. Protein tyrosine kinase 6 (PTK6) promotes survival of endocrine therapy-resistant ER+ breast cancer cells [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P3-04-13.