Targeting Nuclear Transport Pathways To Overcome Endocrine Resistance And Recurrence

Currently, around 75% of patients with breast tumors test positive for estrogen receptor alpha (ERa) and are treated with endocrine therapies, such as tamoxifen. One-third of the breast tumors eventually become refractory, reducing the survival rate for affected patients. A combination of alternative endocrine therapies and kinase inhibitors is currently used in such patients. However, after an initial period of therapy response, these tumors relapse in a more aggressive form. Further, the alternative therapies are not optimal in terms of pharmacological properties, are poorly tolerated, and have side-effects that severely decrease quality of life of the patient. Thus, there is a critical need for novel, targetable, mechanism-based therapeutic strategies that 1) re-sensitize ERa (+) tumors to endocrine therapies, and 2) include diagnostic methods to select patients likely to benefit from this approach. Our objective in this study is to validate a group of nuclear transport genes as biomarkers for endocrine resistance, and to evaluate their inhibition as a novel means to enhance the effectiveness of endocrine therapies. Our central hypothesis is that high expression of these genes in ERa (+) tumors serve as a viable biomarker for risk of endocrine therapy failure. We focused on XPO1, the main nuclear export protein, which exports ERK5 from the nucleus to the cytoplasm and we used selinexor (KPT-330), the inhibitor of XPO1, which is already used in clinical trials for solid and hematological cancers (clinicalTrials.gov). Our experiments show that estradiol induces nuclear localization of ERK5, which otherwise would contribute to increased invasiveness and metastatic potential in the cytoplasm. Selinexor increases ERK5 nuclear localization in tamoxifen resistant breast cancer cell lines. Our hypothesis is that sequestering ERK5 in the cell nucleus and blocking its recycle into the nucleus by selinexor is directly associated with the improved transcriptional response to endocrine therapies. The nuclear export pathways have not previously been implicated in the development of endocrine resistance, and given the need for better strategies for selecting patients to receive endocrine reagents and improving therapy response of relapsed ERa(+) tumors, our findings show high and significant promise for uncovering the role of these pathways and demonstrating their use in reducing cancer recurrences. Citation Format: Eylem Kulkoyluoglu, Kinga Wrobel, Yiru Chen Zhao, Karen L. Chen, Kadriye Hieronymi, Jamie Holloway, Yosef Landesman, Tania Ray, Partha S. Ray, Alexander E. Lipka, Rebecca L. Smith, Zeynep Madak Erdogan. Targeting nuclear transport pathways to overcome endocrine resistance and recurrence. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1812.