Combined inhibition of IL1, CXCR1/2, and TGFβ signaling pathways modulates in-vivo resistance to anti-VEGF treatment

Abstract

Resistance of tumors to antiangiogenic therapies is becoming increasingly relevant. We recently identified interleukin-1 (IL1), CXC receptors (CXCR)1/2 ligands, and transforming growth factor β (TGFβ) among the proinflammatory factors that were expressed at higher levels in murine models resistant to the antivascular endothelial growth factor (anti-VEGF) antibody bevacizumab. Here, we hypothesized that the combined inhibition of these proinflammatory signaling pathways might reverse this anti-VEGF resistance. Bevacizumab-resistant FGBR pancreatic cancer cells were treated in vitro with bevacizumab, the recombinant human IL1 receptor antagonist anakinra, the monoclonal antibody against TGFβ receptor type II TR1, and a novel recombinant antibody binding CXCR1/2 ligands. The FGBR cells treated with these agents in combination had significantly higher levels of E-cadherin and lower levels of vimentin, IL6, phosphorylated p65, and SMAD2, and showed significantly lower migration rates than did their controls treated with the same agents without bevacizumab or with a single agent bevacizumab as a control. Consistently, the combination of these agents with bevacizumab reduced the FGBR tumor burden and significantly prolonged mice survival compared with bevacizumab in monotherapy. Tumors from mice receiving the combination treatment showed significantly lower expression of IL6 and phosphorylated SMAD2, higher expression of E-cadherin and lower levels of vimentin, and a significantly lower infiltration by CD11b cells compared with bevacizumab-treated controls. This study suggests that inhibition of IL1, CXCR1/2, and TGFβ signaling pathways is a potential therapeutic approach to modulate the acquired resistance to anti-VEGF treatment by reversing epithelial-mesenchymal transition and inhibiting CD11b proangiogenic myeloid cells' tumor infiltration.

Modulating TAK1 Expression Inhibits YAP and TAZ Oncogenic Functions in Pancreatic Cancer

“…Orthotopic injection of pancreatic cancer cells was performed as previously described in ref. 25. We did not observe anesthesia-related deaths.…”

Interleukin-1 blockade overcomes erlotinib resistance in head and neck squamous cell carcinoma

“…Anakinra as a single agent was shown to suppress tumor growth of IL-1-producing, but not non-IL-1-producing, tumor cell lines [27] and anakinra has been shown to be effective in combination with other anti-tumor agents in various other disease models [32–35]. Large numbers of patients with chronic inflammatory diseases have safely been using anakinra for a long period of time since its approval by FDA.…”

An FGFR3 Autocrine Loop Sustains Acquired Resistance to Trastuzumab in Gastric Cancer Patients

“…Cells were daily checked by morphology and routinely tested to be mycoplasma free by PCR assay. Generation of GFPþ/luciferaseþ NCI-N87 cell line (13), in vitro cell proliferation assay, wound-healing assay (14), IHC, protein extraction, and Western blotting (15) were performed as previously described, and for further details see Supplementary Materials and Methods.…”