Leveraging microenvironmental synthetic lethalities to treat cancer

Abstract

Treatment resistance leads to cancer patient mortality. Therapeutic approaches that employ synthetic lethality to target mutational vulnerabilities in key tumor cell signaling pathways have proven effective in overcoming therapeutic resistance in some cancers. Yet, tumors are organs composed of malignant cells residing within a cellular and noncellular stroma. Tumor evolution and resistance to anticancer treatment are mediated through a dynamic and reciprocal dialogue with the tumor microenvironment (TME). Accordingly, expanding tumor cell synthetic lethality to encompass contextual synthetic lethality has the potential to eradicate tumors by targeting critical TME circuits that promote tumor progression and therapeutic resistance. In this Review, we summarize current knowledge about the TME and discuss its role in treatment. We outline the concept of tumor cell-specific synthetic lethality and describe therapeutic approaches to expand this paradigm to leverage TME synthetic lethality to improve cancer therapy.

Figure 1. Sensitizing cancer cells with contextually synthetic lethal therapeutics.

Cancer develops within a TME to form an organ that engages in bidirectional communication to promote tumor evolution. Contextually synthetic lethal therapies interrupt this system by targeting stromal cells or molecules within the TME to arrest tumor progression and improve treatment responses that ultimately eradicate the cancer. As an example, hypoxia in the TME inhibits DNA damage repair pathways, making hypoxic cancer cells more sensitive poly-ADP ribose polymerase (PARP) inhibitors. In contrast, conventional synthetic lethal therapies target cancer cells based only on mutational vulnerabilities.

Figure 2. Targeting contextual synthetic lethalities in the TME.

(A) Low-dose antiangiogenesis therapy normalizes tumor vasculature. (B) Leaky vasculature enables affinity targeting of ECM components enriched in tumors. (C) Small-molecule drugs educate myeloid cells to antitumor phenotypes by differentiation or repolarization. Nanoparticle (NP) encapsulation improves delivery to phagocytes. (D) Enzymatic hydrolysis of ECM or inhibition of CAFs debulks tumor ECM, normalizing tumor structure and vascularity.