Abstract P4-08-01: Tumor suppressor PLK2 may serve as a biomarker in triple negative breast cancer for combinational therapy of PLK1 inhibitors with the standard-of-care chemotherapy
Authors: Gao Yang , Kabotyanski Elena , Acosta Deanna , Villegas Elizabeth , Westbrook Thomas F , Perou Charles M , Rosen Jeffrey M 
Published: March 2020

Abstract
Polo-like kinase (PLK) family members play important roles in cell cycle regulation. The founding member PLK1 is oncogenic and preclinically validated as a cancer therapeutic target. Surprisingly, PLK2 is frequently deleted in human breast cancer, preferentially in triple negative breast cancer (TNBC). Pilot studies using an RNAi screen and colony formation assays suggested that PLK2 might act as a tumor suppressor in breast cancer. This paradox stimulated us to investigate the functions of PLK1 and PLK2 in preclinical models and to understand their clinical implications. In preliminary experiments, we found that knockdown of PLK1 mitigated PLK2-deletion induced phenotypes including inhibiting colony formation, and rescued Plk2 null mammary epithelial cell phenotypes in vivo, including gland hyperbranching, epithelial cell hyperproliferation, and abnormal spindle orientation. Furthermore, we demonstrated that PLK2 interacted with PLK1 using a bimolecular fluorescence complementation assay and by co-immunoprecipitation, and using a proximity ligation assay this interaction was shown to occur in prometaphase.
Due to the lack of targeted therapy, chemotherapy, such as carboplatin usually in combination with Taxol, is still one of the only systematic treatments for TNBC. Although PLK2 is frequently deleted in TNBC, there is currently no viable strategy to target this loss of function. The relationship between PLK2 and PLK1 suggests targeting PLK1 might provide a potential target to treat TNBC patients with loss of PLK2. In order to test this hypothesis, we used p53 null mammary epithelial cells as a sensitized background to generate a cohort of p53/Plk2 double null TNBC tumors. RNA-seq analysis showed that these tumors can be classified into three distinct molecular TNBC sublines: luminal-like, basal-like and claudin-low. Combinational treatment with the PLK1 inhibitor Volasertib and carboplatin showed a strong synergistic effect on tumor growth and led to regression of the Plk2/p53 null claudin-low tumors, but not control Plk2+/p53 null claudin-low tumors. The effect of combinational treatment of PLK1 inhibitor and carboplatin on the other two sublines as well as PLK2-low TNBC patient-derived xenograft (PDX) models is currently under investigation. We hope that these preclinical experiments will provide a rationale for the application PLK1 inhibitors in combination with chemotherapy in a subset of TNBC patients with deletion of PLK2. [Supported by Susan G. Komen Foundation grant SAC110031]
Citation Format: Yang Gao, Elena Kabotyanski, Deanna Acosta, Elizabeth Villegas, Thomas F Westbrook, Charles M Perou, Jeffrey M Rosen. Tumor suppressor PLK2 may serve as a biomarker in triple negative breast cancer for combinational therapy of PLK1 inhibitors with the standard-of-care chemotherapy [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P4-08-01.