CXCR4 inhibitor, MSX‐122 suppresses AOM‐induced colon cancer in Apc+/Min mouse

Abstract

IntroductionIn prior studies, we showed that EGFR is required for tumor promotion by Western diet in the azoxymethane (AOM) model of sporadic colon cancer and the AOM/DSS model of inflammation‐associated colon cancer. We also demonstrated that ADAM17, the metalloprotease responsible for shedding membrane‐bound EGFR ligands, controls tumor development in both the AOM and the Apc+/mutant multiple intestinal neoplasia (Min) mouse model. Furthermore, we established that Sdf1a‐CXCR4 signals activated EGFR by an ADAM17‐dependent mechanism in colon cancer cells; and that Western diet up‐regulated Sdf1a‐CXCR4 and ADAM17 in colonic mucosa. We hypothesized that CXCR4 blockade might inhibit colon cancer development. The aim of this study was to test the ability of a novel CXCR4 antagonist, MSX‐122 (substituted benzylamine) to inhibit AOM‐promoted colon cancer in Apc+/Min mice. Min mice without AOM treatment mostly develop small intestinal tumors, whereas AOM‐treated Apc+/Min mice develop colon cancers (Suzui et al 2002).MethodsIn studies in cell culture, we examined the ability of MSX‐122 to block Sdf1a‐induced EGFR transactivation. In vivo, Apc+/Min mice were given AOM (10 mg i.p./kg body weight) and two weeks later mice were started on a Western diet (20% fat). Mice received MSX‐122 i.p. (2.5 mg/kg body weight, n=12) or vehicle (DMSO, n=13) three times weekly and were killed after 10 wks.ResultsMSX‐122 blocked EGFR transactivation by Sdf1a in HT29 colon cancer cells as assessed by reductions in pErbB2, pAKT and pERK. In vivo, MSX‐122 was well tolerated with mice showing comparable weight gain to vehicle‐treated mice. As expected, AOM induced colon tumors in Apc+/Min mice. MSX‐122 significantly reduced colon tumor incidence (92.3% vs. 50.0%, p=0.025) and cancer incidence (69.2% vs. 16.7%, p=0.015). MSX‐122 also reduced tumor burden as assessed by total tumor multiplicity (1.8 vs. 1.0 tumor per TBM; p=0.02), tumor volume (169.5 mm3 vs. 61.2 mm3, p<0.023) and tumor proliferation as assessed by Ki67 staining (37.2±3.6% vs. 25.3±5.8%, p<0.005). Cancer multiplicity also appeared to be decreased (1.6 vs. 1.0 tumor/TBM, p=0.17).ConclusionsMSX‐122 blocked EGFR transactivation by CXCR4 agonist Sdf1a in colon cancer cells. MSX‐122 also inhibited colon tumor development and progression in the AOM‐promoted Apc+/Min mouse model. We speculate that MSX‐122, which was well tolerated in a phase 1b clinical trial (Painter, W. 2015), could serve as a chemopreventive agent in individuals at increased risk for colon cancer.Support or Funding InformationNIH R01CA164124This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.