scholarly journals The epidermal growth factor receptor (EGFR)-S442F mutant displays increased affinity for neuregulin-2β and agonist-independent coupling with downstream signalling events

2006 ◽  
Vol 396 (1) ◽  
pp. 79-88 ◽  
Author(s):  
Jennifer L. Gilmore ◽  
Richard M. Gallo ◽  
David J. Riese

The EGFR (epidermal growth factor receptor; ErbB1) is frequently the subject of genetic changes in human tumours which contribute to the malignant phenotype by altering EGFR signalling. Examples of such genetic changes include overexpression, extracellular domain deletions and point mutations, and small deletions in the tyrosine kinase domain. We hypothesized that a point mutation in one of the EGFR ligand-binding domains would increase the affinity of EGFR for NRG2β (neuregulin-2β), which is not a potent stimulus of signalling by EGFR-Wt (wild-type EGFR). This mutation would permit NRG2β stimulation of EGFR signalling in settings in which NRG2β does not normally do so. To test this hypothesis, we have generated and evaluated various EGFR alleles containing mutations at Val441 and Ser442. NRG2β is a much more potent stimulus of the EGFR-S442F mutant than of EGFR-Wt. Furthermore, the affinity of NRG2β for the EGFR-S442F mutant is greater than the affinity of NRG2β for EGFR-Wt. Finally, the EGFR-S442F mutant constitutively suppresses apoptosis via phosphoinositide 3-kinase and Akt signalling but is not highly tyrosine phosphorylated in the absence of ligand. These results suggest that mutations in the EGFR ligand-binding domain in tumours may permit potent stimulation of EGFR signalling by ligands that are not normally potent EGFR agonists, thereby providing for a novel mechanism by which EGFR signalling may be deregulated. These results also suggest that novel EGFR mutations and signalling activities may be responsible for deregulated EGFR signalling in tumour cells.

2016 ◽  
Vol 104 (1) ◽  
Author(s):  
So-Young Lee ◽  
Jae-Cheong Lim ◽  
Eun-Ha Cho ◽  
Sung-Hee Jung

AbstractKRAS is very commonly mutated resulting in a constitutively activated protein, which is independent of epidermal growth factor receptor (EGFR) ligand binding and resistant to anti-EGFR therapy. Although KRAS is frequently studied, there is still no uniform standard for detecting of KRAS mutations. In this report, a new scintillation proximity assay-based approach is described that determines the relative affinities of wild-type and mutated KRAS to the anti-KRAS antibody. We performed


2015 ◽  
Vol 6 (2) ◽  
pp. 19-23
Author(s):  
Hanan Ezzat Shafik ◽  
Mohamed Ashour

Abstract Introduction: Improvement in the clinical outcome of lung cancer is likely to be achieved by identification of the molecular events that underlie its pathogenesis. The frequency of epidermal growth factor receptor (EGFR) mutations is ethnicity-dependent, with a higher proportion in Asian populations than in whites, while the incidence of EML4-ALK (echinoderm microtubule-associated-protein like 4-anaplastic lymphoma kinase) fusion gene ranged from 1.6% to 16.4% in patients with NSCLC and these individuals were distinct from those harbouring mutations in the epidermal growth factor receptor gene. This study was conducted to determine the frequency of EGFR mutation and EML4-ALK fusion gene in our population and to determine the effect of different clinicopathological features on the expression of those mutations in patients with lung adenocarcinoma. Results: EGFR mutations were detected in approximately 33% of our patients in this series; the most frequently detected mutation was exon 19 deletion. EML4-ALK fusion gene was detected in 7.3% of patients. Conclusion: Our population exhibited the incidence of EGFR mutation approximately similar to that reported in East Asia and Japanese patients, higher than that recorded in USA, and Australia. However, more studies with larger patients’ numbers are needed to verify this finding.


2019 ◽  
Vol 12 (1) ◽  
pp. 178-182 ◽  
Author(s):  
Seigo Minami ◽  
Shouichi Ihara ◽  
Tsunehiro Tanaka ◽  
Hideyasu Okada ◽  
Kazuki Hashimoto ◽  
...  

Uncommon epidermal growth factor receptor (EGFR) gene mutations include G719S, T790M and S768I. T790M gatekeeper mutation is the most frequent mechanism of acquired drug resistance to first- and second-generation EGFR-tyrosine kinase inhibitors (TKIs). Osimertinib is a specific EGFR-TKI to overcome T790M resistance mutation. However, owing to a new drug and a rare mutation type, it remains unknown whether osimertinib is effective for acquired S768I. Herein, we reported a 76 year-old woman with pulmonary adenocarcinoma, which had acquired EGFR mutations of S768I and T790M in addition to original G719S after long gefitinib treatment. These mutations were detected in biopsy specimen of liver metastases. During two months of osimertinib, multiple liver metastases progressively enlarged. This case suggested that acquired S768I mutation might be resistant to osimeritinib, despite of co-occurrence of T790M.


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