Progression of colorectal cancer through epidermal growth factor receptor (EGFR)-independent mechanisms
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AbstractAccording to the American Cancer Society, colorectal cancer (CRC) is the third most common type of cancer with more than 134.000 estimated new cases in 2016. Early detection efforts and more effective therapies have reduced mortality, yet the second mostly deadly cancer in the United States with approximately 50,000 deaths expected this year. Extensive research has revealed multiple genes and significant pathways relevant to CRC progression and development. One of the first and current targets for molecular targeted therapies is the epidermal growth factor receptor (EGFR), a tyrosine kinase receptor, which is involved in growth and tumor proliferation. However, we have observed that efficiency of anti-EGFR therapy is influenced by the genetic background on which colonic tumors arise. Thus, it is imperative to better understand the mechanisms governing molecular heterogeneity of CRC. Preclinical studies in our lab and others have shown that targeting EGFR greatly reduces the incidence of CRC in mouse models. However, primary and secondary resistance to anti-EGFR therapies counts for approximately 80% of the patients with CRC, which suggests that targeting EGFR alone does not result in a significant benefit in most CRC cases. 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. In this study, we used a conditional Egfr allele (Egfrf) to demonstrate the existence of EGFR independent CRCs in mice that have faster growth rates than those with normal EGFR. We also used a metastatic CRC (mCRC) mouse model containing conditionally inactivated Apc alleles (Apcf/f) in combination with a conditionally activatable allele of oncogenic Kras (KrasLSL-G12D) to assess aggressiveness of EGFR-independent versus EGFR-dependent cancers. Adding Egfrf/f to the mCRC model allowed us to analyze the function of EGFR during CRC progression. Following delivery of Cre recombinase-expressing adenovirus (AdCre) to the distal colon of Apcf/f, KrasLSL-G12D/+ mice, approximately 50% of tumors progress into carcinoma in 20 weeks, with liver metastases in greater than 20% of mice 24 weeks after induction. We discovered a 10% increase in the penetrance of CRCs arising in the absence of EGFR. Early endoscopic determination shows an increase in tumor multiplicity in EGFR deficient cancers (Egfrf/f, Apcf/f, KrasLSL-G12D/+) when compared with EGFR containing cancers (Apcf/f, Kras LSL-G12D/+). In addition, biweekly colonoscopies confirmed that colonic tumors grow faster in the absence of EGFR. Monitoring via high-frequency abdominal ultrasound suggests premature liver metastasis (16 weeks after induction) in 20% of mice lacking EGFR. These findings conclusively 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, David Threadgill. Progression of colorectal cancer through epidermal growth factor receptor (EGFR)-independent mechanisms. [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer: From Initiation to Outcomes; 2016 Sep 17-20; Tampa, FL. Philadelphia (PA): AACR; Cancer Res 2017;77(3 Suppl):Abstract nr A15.
