Oncogenic mutant forms of EGFR: Lessons in signal transduction and targets for cancer therapy

Abstract

Edited by Stefan HohmannKeywords: EGFR Mutations Kinase Lung cancer Glioblastoma ErbB a b s t r a c tThe EGF-receptor is frequently mutated in a large variety of tumors. Here we review the most frequent mutations and conclude that they commonly enhance the intrinsic tyrosine kinase activity, or they represent loss-of-function of suppressive regulatory domains. Interestingly, the constitutive activity of mutant receptors translates to downstream pathways, which are subtly different from those stimulated by the wild-type receptor. Cancer drugs intercepting EGFR signaling have already entered clinical application. Both kinase inhibitors specific to EGFR, and monoclonal antibodies to the receptor are described, along with experimental approaches targeting the HSP90 chaperone. Deeper understanding of signaling pathways downstream to mutant receptors will likely improve the outcome of current EGFR-targeted therapies, as well as help develop new drugs and combinations.

Lung Cancer-derived Galectin-1 Enhances Tumorigenic Potentiation of Tumor-associated Dendritic Cells by Expressing Heparin-binding EGF-like Growth Factor

“…Increased expression of EGFR has been reported in over 70% of non-small-cell lung curcinoma and is correlated with poor outcome (30). In addition, abnormal expression of cognate EGFR ligand expression is involved in the development of the EGFR resistance of the antagonist, including receptor mutations, constitutive activation of downstream signaling, and activation of alternative pathways (31). Our data are the first to demonstrate that TADCs are one of the sources of HB-EGF, which, in turn, increases cell proliferation and migration and causes lung cancer cells to undergo EMT.…”

Epidermal Growth Factor Receptor Variant III (EGFRvIII) Positivity in EGFR-Amplified Glioblastomas: Prognostic Role and Comparison between Primary and Recurrent Tumors

“…Several studies have reported on various other EGFR sequence alterations than EGFRvIII in glioblastomas, including SNVs as well as larger rearrangements/deletions affecting the extracellular or intracellular domains (8,14,(57)(58)(59)(60)(61)(62)(63). We therefore additionally investigated 27 pairs of primary and recurrent glioblastomas for other EGFR gene alterations using targeted next-generation sequencing of tumor DNA.…”

Mechanisms for DNA‑damaging agent‑induced inactivation of ErbB2 and ErbB3 via the ERK and p38 signaling pathways

“…Upon activation, ErbB family members form homodimers or heterodimers that serve important roles in biological processes associated with differentiation, proliferation and apoptosis, primarily through mitogen-activated protein kinase and the phosphoinositide-3 kinase/RAC-alpha serine/threonine-protein kinase signaling pathways (2)(3)(4)(5)(6). ErbB mutations are frequently identified in human cancer, leading to aberrant ErbB expression and subsequent survival signals (7). Therefore, drugs targeting the ErbB receptors have been a central focus of cancer research (8,9).…”