Epithelial-specific ERBB3 deletion results in a genetic background-dependent increase in intestinal and colon polyps that is mediated by EGFR

Author summaryTargeted cancer therapeutics that are efficacious in pre-clinical studies do not always translate to the clinic. This can be due to the homogenous pre-clinical models not representing heterogeneous patient populations. Small molecular inhibitors to ERBB3 for colorectal cancer efficiently inhibited tumorigenesis in pre-clinical studies, but in clinical trials failed to show efficacy and even trended toward enhancing cancer growth. Using two mouse colorectal cancer models with variable the genetic backgrounds, we show that epithelial deletion of ERBB3 can result in outcomes ranging from inhibition to enhanced tumor growth. Molecular profiling implicated EGFR as a likely mediator of enhanced tumor growth in the absence of ERBB3. Mice with epithelial deletion of both EGFR and ERBB3 were used to show that the background dependency of ERBB3 is mediated by EGFR. These results show that genetic context of cancer therapeutics can have profound implications on translating pre-clinical results into the clinic. ERBB3 has gained attention as a potential therapeutic target to treat colorectal and other types of cancers. To confirm a previous study showing intestinal polyps are dependent upon ERBB3, we generated an intestinal epithelia-specific ERBB3 deletion in C57BL/6-Apc(Min/+) mice. Contrary to the previous report showing a significant reduction in intestinal polyps with ablation of ERBB3 on a B6;129 mixed genetic background, we observed a significant increase in polyp number with ablation of ERBB3 on C57BL/6J compared to control littermates. We confirmed the genetic background dependency of ERBB3 by also analyzing polyp development on B6129 hybrid and B6;129 advanced intercross mixed genetic backgrounds, which showed that ERBB3 deficiency only reduced polyp number on the mixed background as previously reported. Increased polyp number with ablation of ERBB3 was also observed in C57BL/6J mice treated with azoxymethane showing the effect is model independent. Polyps forming in absence of ERBB3 were generally smaller than those forming in control mice, albeit the effect was greatest in genetic backgrounds with reduced polyp numbers. The mechanism for differential polyp number in the absence of ERBB3 was through altered proliferation. Backgrounds with increased polyp number with loss of ERBB3 showed an increase in cell proliferation even in non-tumor epithelia, while backgrounds showing reduced polyp number with loss of ERBB3 showed reduced cellular proliferation. Increase polyp number caused by loss of ERBB3 was mediated by increased epidermal growth factor receptor (EGFR) expression, which was confirmed by deletion of Egfr. Taken together, this study raises substantial implications on the use of ERBB3 inhibitors against colorectal cancer. The prediction is that some patients may have increased progression with ERBB3 inhibitor therapy, which is consistent with observations reported for ERBB3 inhibitor clinical trials.

Automated summary

This study highlights the discrepancy between pre-clinical efficacy and clinical translation of targeted cancer therapies and the significant impact of genetic background on the response in mouse colorectal cancer models. The genetic background dependency of ERBB3 has implications for polyp growth in the intestines, with implications for the use of ERBB3 inhibitors in colorectal cancer treatment.