Molecular-Targeted Therapies for Epidermal Growth Factor Receptor and Its Resistance Mechanisms

Abstract

Cancer therapies targeting epidermal growth factor receptor (EGFR), such as small-molecule kinase inhibitors and monoclonal antibodies, have been developed as standard therapies for several cancers, such as non-small cell lung cancer, colorectal cancer, pancreatic cancer, breast cancer, and squamous cell carcinoma of the head and neck. Although these therapies can significantly prolong progression-free survival, curative effects are not often achieved because of intrinsic and/or acquired resistance. The resistance mechanisms to EGFR-targeted therapies can be categorized as resistant gene mutations, activation of alternative pathways, phenotypic transformation, and resistance to apoptotic cell death. Analysis of the processes that modulate EGFR signal transduction by EGFR-targeted inhibitors, such as tyrosine kinase inhibitors and monoclonal antibodies, has revealed new therapeutic opportunities and has elucidated novel mechanisms contributing to the discovery of more effective anticancer treatments. In this review, we discuss the roles of EGFR in cancer development, therapeutic strategies for targeting EGFR, and resistance mechanisms to EGFR-targeted therapies, with a focus on cancer therapies for individual patients.

A novel, safe, fast and efficient treatment for Her2‐positive and negative bladder cancer utilizing an EGF‐anthrax toxin chimera

“…S1). This is important as Her2 is known to interfere EGFR internalization and RNA‐seq data from 28 dog bladder tumors ( vs . 4 normal urothelial layer) indicated that Her2 was enriched in dog bladder tumors in these animals (Supporting Information Fig.…”

“…Since internalization of EGFR complexes plays an important role in the success of these targeted agents, the presence of EGFR internalization‐impairing mutations or upregulation of Her2/neu (known to interfere with EGFR endocytosis) are among the factors known to impair the efficacy of EGF‐based strategies …”

“…19 Since bladder cancer cells are known to upregulate epidermal growth factor (EGF) receptor (EGFR) expression, 20 we tested the use of an EGF-targeted bacterial toxin designed to bypass the limitations of other EGF/toxin-based approaches as an antibladder cancer agent: Since EGFR-targeting therapeutics require receptor endocytosis to be active, impaired EGFR uptake (e.g., by Her2/neu upregulation or the presence of mutations affecting EGFR internalization) are predicted to negatively impact their efficacy. [21][22][23] Importantly, to bypass such limitations we previously devised an approach relying on receptor microclustering to induce nanoparticle uptake by bladder tumor cells. 24 These microclustering effects can also be elicited by multivalent agents such as anthrax toxin that, in contrast to monovalent toxins (e.g., diphtheria toxin [25][26][27], forms oligomers at the cell surface promoting its own internalization.…”

Intrinsic and Extrinsic Pharmacokinetic Variability of Small Molecule Targeted Cancer Therapy

“…Some portion of the larger observed variability, in PK exposure for example, will be related to the route of administration because cytotoxic agents are most typically delivered intravenously whereas targeted therapeutics are often administered orally. The consequences of large variability in exposure across patient populations are the risk of (i) poor efficacy due to subtherapeutic exposure, (ii) unpredictable toxicity and adverse events associated with higher than optimal concentrations, and (iii) the development of drug resistance caused by inconsistent or inadequate tumor exposure . To best understand the disposition of a molecularly targeted therapy, it is important to evaluate the degree of interindividual variability of PK parameters in patients with cancer.…”

“…patient populations are the risk of (i) poor efficacy due to subtherapeutic exposure, (ii) unpredictable toxicity and adverse events associated with higher than optimal concentrations, and (iii) the development of drug resistance caused by inconsistent or inadequate tumor exposure. 4,5 To best understand the disposition of a molecularly targeted therapy, it is important to evaluate the degree of interindividual variability of PK parameters in patients with cancer.…”