Abstract 925: PDX models of ER+ endocrine-resistant metastatic breast cancer identify Polo-like kinase 1 (PLK1) as a therapeutic target

Background: Metastatic estrogen receptor positive (ER+) breast cancers (BC) are genetically heterogeneous and a significant proportion of patients display intrinsic or acquired resistance to endocrine treatments, mTOR and CDK4/6 inhibitors. The objective of this study was to identify new therapies in clinically relevant PDX models of metastatic ER+ BC progressing on endocrine treatment and/or palbociclib. Methods: PDX models were generated by engraftment of spinal bone metastases from 120 BC patients. PDXs were molecularly characterized using SNP-arrays, targeted exome sequencing and global gene expression (GEX) analysis. The anti-tumor efficacy of the PLK1 inhibitor volasertib was evaluated in vivo compared to fulvestrant and palbociclib in two PDX models. PLK1 abundance was analyzed by immunohistochemistry in PDXs and compared with the original primary tumor and bone metastasis from each patient. PLK1 expression measured by RT-PCR was assessed in a cohort of 441 BC patients with 15-year follow-up. GEX analysis of PLK1was assessed in patients treated with neoadjuvant anastrazole. Mechanistic studies were performed in a panel of endocrine resistant BC cell lines. Results: Ten PDX have been established, 8 were ER+ and 2 triple-negative (TN). Genomic alterations included mutations in AKT1, PI3KCA, BRCA2, GATA3, NF1, and amplifications of FGFR1, CCND1 and CCNE2. Comparative pathway analysis of bone metastases derived PDX and patients9 primary tumors showed enrichment for pathways associated with mitotic nuclear division, chromatid segregation and G2/M transition. PLK1 was the top commonly up-regulated gene within these pathways. Treatment of an endocrine-resistant ER+ PDX, harboring amplification of CCND1, CCNE2, FGFR1 and high expression of CDK1, showed only partial response to palbociclib and resistance to the FGFR inhibitor, AZD4547. However, PLK1 inhibitor volasertib induced rapid tumor shrinkage and complete response within 5 weeks. Importantly, volasertib was also highly effective when tested as second line therapy in palbociclib pre-treated xenografts. In-vitro inhibition of PLK1 by siRNA or volasertib inhibited tumor proliferation without affecting the expression of ER-regulated genes, suggesting an ER-independent function of PLK1 in regulating cell proliferation. Assessment of the clinical validity of PLK1 expression, revealed a strong association with poor metastases free survival (p Conclusion: We show that inhibition of PLK1 is a new potential treatment strategy for metastatic ER+ BC. Additional experiments are ongoing in PDX and cell lines to investigate G2/M phase dependence of ER+ BC and to identify predictive biomarkers. Citation Format: Elodie Montaudon, Joanna Nikitorowicz-Buniak, Laura Sourd, Rania El Botty, Ahmed Dahmani, Lea Huguet, Ludivine Morriset, Pierre Painsec, Fariba Nemati, Sophie Vacher, Sophie Chateau-Joubert, Sunil Pancholi, Camilla Rega, Ricardo Ribas, Andre Nicolas, Didier Meseure, Anne Salomon, Zakia Tariq, Keltouma Driouch, Florence Coussy, Guillaume Dutertre, Paul Cottu, Ivan Bieche, Lesley-Ann Martin, Elisabetta Marangoni. PDX models of ER+ endocrine-resistant metastatic breast cancer identify Polo-like kinase 1 (PLK1) as a therapeutic target [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 925.