Polypharmacologic Reprogramming of Tumor-Associated Macrophages toward an Inflammatory Phenotype

Tumor-associated macrophages (TAM) are an important component of the tumor microenvironment (TME) that can promote tumor progression, metastasis, and resistance to therapies. Although TAMs represent a promising target for therapeutic intervention, the complexity of the TME has made the study of TAMs challenging. Here, we established a physiologically relevant in vitro TAM polarization system that recapitulates TAM protumoral activities. This system was used to characterize dynamic changes in gene expression and protein phosphorylation during TAM polarization and to screen phenotypic kinase inhibitors that impact TAM programming. BMS-794833, a multitargeted compound, was identified as a potent inhibitor of TAM polarization. BMS-794833 decreased protumoral properties of TAMs in vitro and suppressed tumor growth in mouse triple-negative breast cancer models. The effect of BMS-794833 was independent of its primary targets (MET and VEGFR2) but was dependent on its effect on multiple signaling pathways, including focal adhesion kinases, SRC family kinases, STAT3, and p38 MAPKs. Collectively, these findings underline the efficacy of polypharmacologic strategies in reprogramming complex signaling cascades activated during TAM polarization. SIGNIFICANCE: A physiologically relevant in vitro system of TAM polarization uncovers signaling pathways that regulate polarization and identifies strategies to target macrophage reprogramming to suppress cancer growth.

 

Comments:

This research is incredibly promising in understanding and potentially targeting tumor-associated macrophages (TAMs) within the tumor microenvironment (TME). By establishing an in vitro system mimicking TAM behavior, researchers were able to observe dynamic changes in gene expression and protein phosphorylation during TAM polarization.

The discovery of BMS-794833 as a potent inhibitor of TAM polarization is particularly noteworthy. Its ability to decrease the protumoral properties of TAMs in vitro and suppress tumor growth in triple-negative breast cancer models suggests its potential as a therapeutic agent.

Moreover, the independence of BMS-794833's effect on its primary targets (MET and VEGFR2) but its dependence on various signaling pathways, such as focal adhesion kinases, SRC family kinases, STAT3, and p38 MAPKs, highlights the complexity of TAM polarization and the need for polypharmacologic strategies to address it effectively.

This study's significance lies in its establishment of a physiologically relevant system for studying TAM behavior and identifying potential therapeutic targets to reprogram macrophages and inhibit cancer growth. It opens avenues for further exploration and development of strategies to modulate TAMs in the TME for improved cancer therapies.

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Cat.No.	Product Name	Information
S2201	BMS-794833	BMS-794833 is a potent ATP competitive inhibitor of Met (c-Met)/VEGFR2 with IC50 of 1.7 nM/15 nM, also inhibits Ron, Axl and Flt3 with IC50 of <3 nM; a prodrug of BMS-817378. Phase 1.

Related Targets

VEGFR c-Met RON