Immune Resistance and EGFR Antagonists in Colorectal Cancer

Abstract

: Targeting the epidermal growth factor receptor (EGFR) either alone or in combination with chemotherapy in patients with RAS wild type metastatic colorectal cancer (mCRC) has revolutionized the treatment of CRC, but with less results than initially envisaged. In recent years, the discovery of multiple pathways leading to the escape from anti-EGFR therapy has revealed an enormous complexity and heterogeneity of human CRC due to the intrinsic genomic instability and immune/cancer cell interaction. Therefore, understanding the mechanistic basis of acquired resistance to targeted therapies represents a major challenge to improve the clinical outcomes of patients with CRC. The latest findings strongly suggest that complex molecular alterations coupled with changes of the immune tumor microenvironment may substantially contribute to the clinical efficacy of EGFR antagonist. In this review, we discuss the most recent findings that contribute to both primary and acquired anti-EGFR therapy resistance. In addition, we analyze how strategies aiming to enhance the favorable effects in the tumor microenvironment may contribute to overcome resistance to EGFR therapies.

Keywords: EGFR; colorectal cancer; immune microenvironment; resistance; targeted therapies.

Figure 1

Aberrant genetic alterations implicated in the resistance to anti-EGFR therapy. Anti-EGFR targeted therapy is combined with other cancer treatments in patients with advanced colorectal cancer bearing wild type RAS. While patients respond fairly well initially, in most cases sustained treatment typically results in the failure of the response to treatment and a poor prognosis. This therapy acting as a selection pressure, enables tumor cells to acquire extensive genetic alterations, leading to abnormal activation or amplification of different tyrosine kinase receptors (upstream) and downstream signaling pathways dependent or independent of EGFR signaling. These mechanisms can be expanded through parallel evolution, enabling tumor cells to adapt, while maintaining their intratumoral heterogeneity that contributes to tumorigenesis.

Figure 2

Tumor microenvironment (TME) is a key determinant for the response to anti-EGFR therapy. Tumors are complex adaptive systems owing to the heterogeneous nature of cancer cells and surrounding immune cell populations (T lymphocytes, myeloid cells, natural killer). In the clonal evolution model, from a founder cell, different subclones (represented by different colors) emerge due to genetic and epigenetic alterations resulting in the intratumor heterogeneity. EGFR and its ligands are differentially expressed in the tumor and surrounding immune cell populations. This heterogeneity can significantly affect the effectiveness of targeted therapies. Currently, immunotherapy (Anti-PD1) is restricted to a CRC subgroup harboring loss of mismatch-repair (MMR) proteins. Other CRCs do not meaningfully respond to any traditional immunotherapy approach, including checkpoint blockade, adoptive cell transfer, and vaccination. In the future, pathways and molecules determining the immunological profiling of tumor subtypes might be targeted together with anti-EGFR for therapeutic immune interventions. Abbreviations: microsatellite instable high (MSI-H); JAK, Janus kinase; Histone deacetylases (HDAC).