Oncogenic fingerprint of epidermal growth factor receptor pathway and emerging epidermal growth factor receptor blockade resistance in colorectal cancer

Abstract

Epidermal growth factor receptor (EGFR) has been an attractive target for treatment of epithelial cancers, including colorectal cancer (CRC). Evidence from clinical trials indicates that cetuximab and panitumumab (anti-EGFR monoclonal antibodies) have clinical activity in patients with metastatic CRC. The discovery of intrinsic EGFR blockade resistance in Kirsten RAS (KRAS)-mutant patients led to the restriction of anti-EGFR antibodies to KRAS wild-type patients by Food and Drug Administration and European Medicine Agency. Studies have since focused on the evaluation of biomarkers to identify appropriate patient populations that may benefit from EGFR blockade. Accumulating evidence suggests that patients with mutations in EGFR downstream signaling pathways including KRAS, BRAF, PIK3CA and PTEN could be intrinsically resistant to EGFR blockade. Recent whole genome studies also suggest that dynamic alterations in signaling pathways downstream of EGFR leads to distinct oncogenic signatures and subclones which might have some impact on emerging resistance in KRAS wild-type patients. While anti-EGFR monoclonal antibodies have a clear potential in the management of a subset of patients with metastatic CRC, further studies are warranted to uncover exact mechanisms related to acquired resistance to EGFR blockade.

miR-15b-5p resensitizes colon cancer cells to 5-fluorouracil by promoting apoptosis via the NF-κB/XIAP axis

“…A critical factor that inevitably limits the efficacy of chemotherapy is drug resistance, which can be classified into intrinsic and acquired resistance. Not surprisingly, acquired resistance is more frequent during the course of anticancer drug treatment including chemotherapy and targeted therapies 5 , 6 ; many cancer patients who initially respond well to chemotherapy gradually exhibit decreased sensitivity to the specific chemotherapeutic. This acquired resistance may be attributed to long-term drug exposure, resulting in the development of mutations or adaptive processes; however, the mechanisms underlying such chemoresistance remain to be fully elucidated.…”

The Immunogenicity and Anti-Tumor Efficacy of a Rationally Designed EGFR Vaccine

“…The receptor is composed of an extracellular ligand-binding domain (ECD), a helical transmembrane domain, and a cytoplasmic signaling domain. Upon binding to its ligands such as epidermal growth factor (EGF) and transforming growth factor alpha (TGF-α), the receptor is dimerized, which activates the receptor tyrosine kinase, and in turn it initiates several signaling cascades such as RAS-RAF-MEK-ERK, phosphotidylinositol-3 kinase-Akt, PLCgamma-PKC etc, which contribute to cell proliferation, angiogenesis, and apoptosis resistance [1, 2]. …”

Anticancer Properties of N,N-dibenzylasparagine as an Asparagine (Asp) analog, Using Colon Cancer Caco-2 Cell Line

“…Anticancer Properties of N,N-dibenzylasparagine as an Asparagine (Asp) analog, Using Colon Cancer Caco-2 Cell Line and malignancy transformation (Sobani et al, 2016;Balcik-Ercin et al, 2020). Colon cancer is one of the most commonly diagnosed cancers and a leading cause of cancer death worldwide.…”