EGFR-mutated lung cancer: a paradigm of molecular oncology

Abstract

The development of EGFR tyrosine kinase inhibitors for clinical use in non-small cell lung cancer and the subsequent discovery of activating EGFR mutations have led to an explosion of knowledge in the fields of EGFR biology, targeted therapeutics and lung cancer research. EGFR-mutated adenocarcinoma of the lung has clearly emerged as a unique clinical entity necessitating the routine introduction of molecular diagnostics into our current diagnostic algorithms and leading to the evidence-based preferential usage of EGFR-targeted agents for patients with EGFR-mutant lung cancers. This review will summarize our current understanding of the functional role of activating mutations, key downstream signaling pathways and regulatory mechanisms, pivotal primary and acquired resistance mechanisms, structure-function relationships and ultimately the incorporation of molecular diagnostics and small molecule EGFR tyrosine kinase inhibitors into our current treatment paradigms.

A Predictive Model for Personalized Therapeutic Interventions in Non-small Cell Lung Cancer

“…In an attempt to target this molecule, molecules which compete with ATP binding to the tyrosine kinase domain of EGFR were tested and developed [4]. Currently, gefitinib (Iressa®, AstraZeneca) and erlotinib (Tarceva®, Roche) are the two EGFR tyrosine kinase inhibitors (EGFR-TKI) that have been approved for use in clinical practice [5]. Patients with somatic mutations in exons 18-21 of the tyrosine kinase domain of EGFR show marked response to gefitinib and erlotinib [6], [7].…”

Taking a Back Door to Target Myc

“…Targeted therapies frequently fail because cancer cells compensate for, and evolve around, the drug-induced blockage ( 13). Such relapses are a tragic by-product of the fact that biological "wetwear" is inherently noisy and works reliably only because signaling networks have evolved to be robust, self-correcting, and functionally degenerate.…”

USP8: a novel therapeutic target for Cushing’s disease

“…EGFR in Cushing's disease EGFR (also named as ErbB1), a member of the human epidermal growth factor receptor (HER)/ErbB family of transmembrane receptor tyrosine kinases (RTKs), plays a critical role in regulating cell proliferation, migration, and differentiation [32,33]. Dysregulation of EGFR activity by oncogenic mechanisms, like increased EGFR copy number, EGFR protein overexpression, and activating gene mutations, is thought to activate downstream signaling pathways (e.g., mitogen-activated proteins kinase), which may enhance cellular metabolism, proliferation, and counteract apoptosis, resulting in disease [34].…”