Abstract B47: Systems-level dissection of tumor-macrophage crosstalk in ovarian cancer resistance to MEK inhibition

Several subtypes of ovarian cancer are associated with dysregulated MAPK signaling, including low-grade serous ovarian carcinoma (LGSOC), yet targeted inhibitors of the MAPK pathway have shown relatively limited success in clinical trials for gynecologic malignancies. Here, we investigated whether this could be explained in part by crosstalk between ovarian cancer cells and neighboring tumor-associated macrophages (TAMs) within the tumor microenvironment. Using in vitro models, human ovarian cancer cell lines were mildly protected against MEK inhibitor-induced cell killing by transwell co-culture with alternatively activated (IL-4 stimulated), but not classically activated (LPS and IFN-gamma stimulated), primary monocyte-derived macrophages. We employed multiplexed bead-based immunoassays to acquire a compendium of over 1,200 phosphoprotein, cytokine, and growth factor measurements across combinations of 3 ovarian cancer cell lines and macrophages derived from 4 healthy peripheral mononuclear blood cell (PBMC) donors. Principal components analysis (PCA) and partial least squares regression (PLSR) revealed that compensatory receptor tyrosine kinase signaling occurs in tumor cells upon MEK inhibitor treatment, and that this is amplified upon co-culture with alternatively activated macrophages. Further work will determine if targeting these tumor-intrinsic and crosstalk effects in combination with MEK inhibition represents a potential therapeutic strategy. Citation Format: Stephanie J. Wang, Miles A. Miller, Douglas A. Lauffenburger. Systems-level dissection of tumor-macrophage crosstalk in ovarian cancer resistance to MEK inhibition [abstract]. In: Proceedings of the AACR Special Conference on Targeting RAS-Driven Cancers; 2018 Dec 9-12; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(5_Suppl):Abstract nr B47.