Abstract P1-08-17: Melk expression is associated with immune cell infiltration and pathological compete response (pcr) after neoadjuvant chemotherapy in breast cancer

Abstract

Abstract In experimental settings, maternal embryonic leucine zipper kinase (MELK), an apical member of the snf1/AMPK serine-threonine kinases family, is highly expressed in several malignancies, and plays a role in cell cycle and proliferation in cell culture settings. However, there is no clear insight on the underlying mechanism or association of MELK expression with several key players in the tumor microenvironment (TME) in regulating cancer progression and response to several drugs in the human tumor. We investigated the clinical relevance of MELK expression by performing silico analyses of 7,135 breast cancer patients using multiple independent large cohorts in this study. We found that MELK expression was significantly correlated with tumor growth assessed by American Joint Committee Cancer (AJCC) stage (p < 0.001), Nottingham histological grade (both p < 0.001), MKI67 expression (spearman rank correlation (r) = 0.704 and 0.888, respectively, both p < 0.001), triple-negative breast cancer (TNBC) subtype (both p < 0.001) and also with cell proliferation-related gene sets (all normalized enrichment score (NES) > 1.70, all false discovery rate (FDR) < 0.01) using gene set enrichment analysis (GSEA), in two large cohorts METABRIC and GSE96058. Furthermore, we observed worse patient survival (both p < 0.001), high mutation rate (all p < 0.03), and enhanced cancer cell survival pathways, including MTORC1 signaling, DNA repair and unfolded protein response (all NES > 1.50) in high MELK expression breast cancer. Additionally, breast cancer with high MELK expression was significantly enriched in immune-related gene sets, including allograft rejection, interferon (IFN)-α response and IFN-γ response (all NES > 1.30). Furthermore, infiltration of anti-cancer immune cells (CD4+ memory T cells, T helper type1 cells, CD8+ T cells, M1 macrophages, gamma-delta T cells, and dendritic cells) and pro-cancer (T helper type 2 cells and regulatory T cells), calculated by xCell algorithm, was associated with high MELK expression. High immune cell killing activity (CYT) was also significantly associated with high MELK expression. Although MELK expression did not correlate with sensitivity of any drug tested in cell lines, high MELK was significantly associated with high pathological complete response (pCR) rate after neoadjuvant chemotherapy (NAC) not only in TNBC (area under the curve (AUC) = 0.78, 0.81, and 0.93, respectively), the aggressive breast cancer subtype known to be associated with around 30-40% pCR, but also in ER-positive plus HER2-negative breast cancer (AUC = 0.62, 0.75, and 0.80, respectively), a subtype of breast cancer where pCR rates are very low, in three cohorts GSE25066, GSE20194 and HESS cohorts. In conclusion, our study shows that high MELK expression is significantly associated with cell proliferation, immune cell infiltration, and higher incidence of response to NAC both in ER-positive/HER2-negative and TNBC. Citation Format: Masanori Oshi, Shipra Gandhi, Michelle R Huyser, Yoshihisa Tokumaru, Li Yan, Rongrong Wu, Akimitsu Yamada, Itaru Endo, Kazuaki Takabe. Melk expression is associated with immune cell infiltration and pathological compete response (pcr) after neoadjuvant chemotherapy in breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-08-17.