scholarly journals Revisiting Epidermal Growth Factor Receptor (EGFR) Amplification as a Target for Anti-EGFR Therapy: Analysis of Cell-Free Circulating Tumor DNA in Patients With Advanced Malignancies

2019 ◽  
pp. 1-14 ◽  
Author(s):  
Shumei Kato ◽  
Ryosuke Okamura ◽  
Manvita Mareboina ◽  
Suzanna Lee ◽  
Aaron Goodman ◽  
...  
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Checkpoint Inhibitors ◽  
Growth Factor Receptor ◽  
Egfr Inhibitors ◽  
Mitogen Activated Protein Kinase ◽  
Egfr Amplification ◽  
Epidermal Growth ◽  
Tumor Dna

Purpose To date, evidence for tissue epidermal growth factor receptor (EGFR) overexpression as a biomarker for anti-EGFR therapies has been weak. We investigated the genomic landscape of EGFR amplification in blood-derived cell-free tumor DNA (cfDNA) across diverse cancers and the role of anti-EGFR therapies in achieving response. Methods We assessed EGFR amplification status among 28,584 patients with malignancies evaluated by clinical-grade next-generation sequencing (NGS) of blood-derived cfDNA (54- to 73-gene panel). Furthermore, we curated the clinical characteristics of 1,434 patients at the University of California San Diego who had cfDNA testing by this NGS test. Results Overall, EGFR amplification was detected in cfDNA from 8.5% of patients (2,423 of 28,584), most commonly in colorectal (16.3% [458 of 2,807]), non–small-cell lung (9.0% [1,096 of 12,197]), and genitourinary cancers (8.1% [170 of 2,104]). Most patients had genomic coalterations (96.9% [95 of 98]), frequently involving genes affecting other tyrosine kinases (72.4% [71 of 98]), mitogen-activated protein kinase cascades (56.1% [55 of 98]), cell-cycle–associated signals (52.0% [51 of 98]), and the phosphoinositide 3-kinase pathway (35.7% [35 of 98]). EGFR amplification emerged in serial cfDNA after various anticancer therapies (n = 6), including checkpoint inhibitors (n = 4), suggesting a possible role for these amplifications in acquired resistance. Nine evaluable patients with EGFR amplification were treated with anti-EGFR–based regimens; five (55.6%) achieved partial responses, including three patients whose tissue NGS lacked EGFR amplification. Conclusion EGFR amplification was detected in cfDNA among 8.5% of 28,584 diverse cancers. Most patients had coexisting alterations. Responses were observed in five of nine patients who received EGFR inhibitors. Incorporating EGFR inhibitors into the treatment regimens of patients harboring EGFR amplification in cfDNA merits additional study.

scholarly journals Structure-based design of some quinazoline derivatives as epidermal growth factor receptor inhibitors

2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Muhammad Tukur Ibrahim ◽  
Adamu Uzairu ◽  
Gideon Adamu Shallangwa ◽  
Sani Uba
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Tyrosine Kinase ◽  
Growth Factor Receptor ◽  
Pharmacokinetic Profile ◽  
Egfr Inhibitors ◽  
Tyrosine Kinase Receptor ◽  
Egfr Tyrosine Kinase ◽  
Epidermal Growth

Abstract Background The discovery of epidermal growth factor receptor (EGFR) inhibitors for the treatment of lung cancer, most especially non-small cell lung cancer (NSCLC), was one of the major challenges encountered by the medicinal chemist in the world. The treatment of EGFR tyrosine kinase to manage NSCLCs becomes an urgent therapeutic necessity. NSCLC was the foremost cause of cancer mortality worldwide. Therefore, there is a need to develop more EGFR inhibitors due to the development of drug resistance by the mutation. This research is aimed at designing new EGFR inhibitors using a structure-based design approach. Structure-based drug design comprises several steps such as protein structure retrieval and preparation, ligand library preparation, docking, and structural modification on the best hit compound to design new ones. Result Molecular docking virtual screening on fifty sets of quinazoline derivatives/epidermal growth factor receptor inhibitors against their target protein (EGFR tyrosine kinase receptor PDB entry: 3IKA) and pharmacokinetic profile predictions were performed to identify hit compounds with promising affinities toward their target and good pharmacokinetic profiles. The hit compounds identified were compound 6 with a binding affinity of − 9.3 kcal/mol, compounds 5 and 8, each with a binding affinity of − 9.1 kcal/mol, respectively. The three hit compounds bound to EGFR tyrosine kinase receptor via four different types of interactions which include conventional hydrogen bond, carbon-hydrogen bond, electrostatic, and hydrophobic interactions, respectively. The best hit (compound 6) among the 3 hit compounds was retained as a template and used to design sixteen new EGFR inhibitors. The sixteen newly designed compounds were also docked into the active site of EGFR tyrosine kinase receptor to study their mode of interactions with the receptor. The binding affinities of these newly designed compounds range from − 9.5 kcal/mol to − 10.2 kcal/mol. The pharmacokinetic profile predictions of these newly designed compounds were further examined and found to be orally bioavailable with good absorption, low toxicity level, and permeable properties. Conclusion The sixteen newly designed EGFR inhibitors were found to have better binding affinities than the template used in the designing process and afatinib the positive control (an FDA approved EGFR inhibitor). None of these designed compounds was found to violate more than the permissible limit set by RO5. More so, the newly designed compounds were found to have good synthetic accessibility which indicates that these newly designed compounds can be easily synthesized in the laboratory.

Antibiotics in prevention of skin toxic reactions of epidermal growth factor receptor inhibitors (literature review)

2021 ◽  
pp. 8-11
Author(s):  
L. S. Kruglova ◽  
I. A. Koroleva
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Topical Therapy ◽  
Growth Factor Receptor ◽  
Skin Toxicity ◽  
Egfr Inhibitors ◽  
Tetracycline Antibiotics ◽  
Negative Effect ◽  
Epidermal Growth

The article is an overview and contains up-to-date information on the use of tetracycline antibiotics in the prevention of acne-like rash in patients receiving therapy with epidermal growth factor receptor inhibitors. According to studies, prevention of skin toxicity is necessary to maintain the effectiveness of the antitumor effect of EGFR inhibitors and to minimize the negative effect of adverse effects from the skin on the quality of life of patients. The use of tetracycline antibiotics in combination with topical therapy and photoprotection for the prevention of acne-like rash against the background of the use of EGFR inhibitors is a fairly safe method for long-term use. Of the antibacterial drugs for the prevention of acne-like rash, the most advisable is the appointment of doxycycline at a dose of 100 mg per day from the first day of taking EGFR inhibitors.

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