Abstract 3400: Progression of epidermal growth factor receptor (EGFR)-independent colorectal cancer

Abstract

When combined with standard of care treatment for colorectal cancer (CRC), the use of monoclonal antibodies or small molecule inhibitors against epidermal growth factor receptor (EGFR) show modest efficacy in the clinic. Early detection efforts and more effective therapies have reduced mortality, yet CRC remains the second mostly deadly cancer in the United States with approximately 50,000 deaths expected this year. Thus, it is imperative to better understand the mechanisms governing molecular progression of CRC. Primary and secondary resistance to anti-EGFR therapies occurs in approximately 80% of the patients with CRC. Mutations in Kras explain some non-responding CRCs, but even in cancers lacking Kras mutations, little is known about which cancers are likely to respond to EGFR targeted treatment, suggesting an alternative and EGFR-independent CRC progression mechanism. In this study, we used a conditional Egfr allele (Egfr^f) within the Apc^Min/+ mouse model and identified EGFR-independent tumors with faster growth rates than those developing in EGFR-wild type mice. To assess aggressiveness of EGFR-independent tumors, we used a metastatic CRC mouse model containing conditionally inactivated Apc alleles (Apc^f/f) in combination with a conditionally active allele of Kras (Kras^LSL-G12D). It has been reported that delivery of Cre recombinase-expressing adenovirus to the distal colon of these mice results in tumors that progress to carcinoma within 20 weeks, and liver metastases develop in approximately 20% of mice at 24 weeks. We discovered a 10% increase in the penetrance of tumors arising in the absence of EGFR (Egfr^f/f, Apc^f/f, Kras^LSL-G12D/+). Endoscopic analysis suggests an increase in tumor multiplicity in EGFR-deficient tumors when compared with tumors developing in EGFR-wild-type mice. Biweekly colonoscopies confirmed that colonic tumors have a faster growth rate in the absence of EGFR. High-frequency abdominal ultrasound suggests liver metastasis at 16 weeks in 20% of mice lacking EGFR. These findings demonstrate the existence of an EGFR-independent mechanism by which CRC can arise and progress. Moreover, tumors lacking EGFR grow larger than those developing under normal EGFR activity and may be a more aggressive form of CRC. We also have evidence that ERBB3 and ERBB4, related EGFRs, mediate compensatory and alternative pathways, suggesting an important role for these receptors in the progression of EGFR-independent CRC. This study will advance our understanding of ERBB family biology during colonic tumorigenesis, ultimately contributing to better therapies for CRC.

Citation Format: Carolina Mantilla Rojas, Yu Ming, David Threadgill. Progression of epidermal growth factor receptor (EGFR)-independent colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3400. doi:10.1158/1538-7445.AM2017-3400