Molecular insight of regorafenib treatment for colorectal cancer

Abstract

Regorafenib is a multi-targeting kinase inhibitor approved for the treatment of metastatic colorectal cancer patients in refractory to standard chemotherapy. Similarly to sorafenib, this agent was originally developed as a RAF1 inhibitor. However, the kinase inhibitory profile is distinct from sorafenib. A broad-spectrum of kinase inhibition induces wide-range drug sensitivity, irrespective of mutation status of major oncogenes. This agent's main therapeutic effects are anti-angiogenesis and the remodeling of tumor microenvironment through several mechanisms of action. The dual blockade of VEGF receptors and TIE2 can lead to both additive anti-angiogenesis effects and the suggestive unique regulation of vessel stability. Additionally, it inhibits molecular escape pathways to VEGF inhibition (e.g., FGF, PIGF, and PDGF signaling), enabling its continuous antiangiogenic effect even in tumors resistant to VEGF inhibitors. Furthermore, regorafenib has the important effect of enhancing anti-tumor immunity via macrophage modulation. Based on this concept, clinical trials have been recently launched for the development of a combination strategy with immune checkpoint inhibitors. Contrary to regorafenib induced clinical benefits and advances in the novel strategy, currently no predictive biomarkers have been identified. In the present review, we revisit and summarize regorafenib's unique mechanisms of action. The review could highlight molecular insights and provide some perspective for the search of predictive biomarkers used in metastatic colorectal cancer patients treated with regorafenib.

Keywords: Anti-angiogenesis; Biomarker; Colorectal cancer; Immunotherapy; Regorafenib; Tumor microenvironment.

Fig. 1.. Anti-tumor mechanisms of regorafenib.

Regorafenib inhibits a broad range of activated pathways related to angiogenesis, metastasis, cell proliferation, and immunosuppression. This provides putative mechanisms for its anti-tumor efficacy in CRC.

Fig. 2.. Different regulation of angiogenesis and vessel stability between VEGF and angiopoietin signaling, relating to regorafenib action.

Both VEGF-VEGFR2 and ANG1-TIE2 pathways are pro-angiogenic. However, they have opposite effects on vascular stabilization. Specifically, VEGF-VEGFR2 signaling activates Src-dependent internalization of VE-cadherin. Therefore, it promotes the disruption of interendothelial adherens junctions. Meanwhile, ANG1-TIE2 signaling activates downstream RhoA and mDia limiting the access of Src to VEGFR2. As a consequence, it strengthens vasculature integrity. In tumors, ANG2 acts as an antagonist of ANG1-TIE2 pathway. Specifically, it prompts vessel destabilization and pericyte dropout. ANG2-TIE2 signaling induces angiogenesis in VEGF’s presence, while it leads to vessel regression in VEGF’s absence. TIE1 is an orphan receptor, interacting with TIE2. Regorafenib inhibits both VEGFR2 and TIE2.

Fig. 3.. TME modulation and promotion of anti-tumor immunity by regorafenib.

Several TME’s components promote an immune suppressive environment. Regorafenib modulates immuno-suppressive TME by blocking VEGFRs, TIE2, and CSF-1R, enhancing anti-tumor immunity. Abbreviations: CTL, cytotoxic T lymphocyte; DC, dendric cell; EC, endothelial cell; TAM, tumor-associated macrophage; TEM, TIE2-expressing monocyte/macrophage; TME, tumor microenvironment; Treg, regulatory T cell.