Abstract LB-A03: Molecular systems-guided imaging of multicellular in situ adaptation to targeted therapy in BRAF-mutant cancer

Abstract

Abstract Adaptive signaling through receptor tyrosine kinases (RTKs) has been highly implicated in the resistance to drugs targeting constitutive RAS/RAF/MEK/ERK signaling, particularly in malignancies with constitutive V600 BRAF mutation. However, it has been difficult to systematically understand how such RTK-mediated bypass signaling is influenced by dynamic and localized interactions between tumor cells and neighboring stromal and immune populations. Here we present a pipeline that combines single-cell and bulk transcriptomic analysis from patients, with systems-level mapping of phosphosignaling pathways in co-cultures, to guide the longitudinal in vivo confocal (intravital) microscopy of adaptive bypass signaling in mouse models of BRAF-mutant cancer. This pipeline prioritizes key myeloid populations and phosphosignaling activities (including of ERK) to image in vivo. Intravital microscopy reveals how therapy-induced myeloid accumulation simultaneously shapes the local activity of multiple co-regulated signaling pathways in neighboring cancer cells, in a RTK-dependent manner. Overall, this work offers an integrative approach to quantitating multiple single-cell signaling pathway activities in the tumor microenvironment, and directly images the dynamics with which known cancer-cell autonomous mechanisms of targeted therapy resistance can be locally amplified by neighboring immune cell populations. Citation Format: Stephanie Wang, Ralph Weissleder, Douglas Lauffenburger, Miles Miller. Molecular systems-guided imaging of multicellular in situ adaptation to targeted therapy in BRAF-mutant cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr LB-A03. doi:10.1158/1535-7163.TARG-19-LB-A03