scholarly journals Sequential use of vinorelbine followed by gefitinib enhances the antitumor effect in NSCLC cell lines poorly responsive to reversible EGFR tyrosine kinase inhibitors

2015 ◽  
Vol 137 (12) ◽  
pp. 2947-2958 ◽  
Author(s):  
M.G. Dal Bello ◽  
A. Alama ◽  
G. Barletta ◽  
S. Coco ◽  
A. Truini ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Cell Lines ◽  
Antitumor Effect ◽  
Kinase Inhibitors ◽  
Nsclc Cell ◽  
Egfr Tyrosine Kinase ◽  
Egfr Tyrosine Kinase Inhibitors

scholarly journals Rapidly Acquired Resistance to EGFR Tyrosine Kinase Inhibitors in NSCLC Cell Lines through De-Repression of FGFR2 and FGFR3 Expression

PLoS ONE ◽  
2010 ◽  
Vol 5 (11) ◽  
pp. e14117 ◽  
Author(s):  
Kathryn E. Ware ◽  
Marianne E. Marshall ◽  
Lydia R. Heasley ◽  
Lindsay Marek ◽  
Trista K. Hinz ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Cell Lines ◽  
Kinase Inhibitors ◽  
Acquired Resistance ◽  
Nsclc Cell ◽  
Egfr Tyrosine Kinase ◽  
Egfr Tyrosine Kinase Inhibitors

scholarly journals CSIG-06. DEPATUXIZUMAB MAFODOTIN (ABT-414)-INDUCED GLIOBLASTOMA CELL DEATH REQUIRES EGFR OVEREXPRESSION, BUT NOT PHOSPHORYLATION

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi45-vi45
Author(s):  
Caroline von Achenbach ◽  
Vincent Blot ◽  
William Weiss ◽  
Michael Weller
Keyword(s):  
Cell Death ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Cell Lines ◽  
Glioma Cell ◽  
Kinase Inhibitors ◽  
Glioblastoma Cell ◽  
Egfr Tyrosine Kinase ◽  
Egfr Tyrosine Kinase Inhibitors ◽  
Antibody Drug

Abstract Glioblastomas commonly (40%) exhibit epidermal growth factor receptor (EGFR) amplification, half of these tumors carry the EGFRvIII deletion variant characterized by an in-frame deletion of exons 2–7, resulting in constitutive EGFR activation. Although EGFR tyrosine kinase inhibitors had only modest effects in glioblastoma, novel therapeutic agents targeting amplified EGFR or EGFRvIII continue to be developed. Depatuxizumab mafodotin (ABT-414) is an antibody drug conjugate consisting of the monoclonal antibody 806 and, as its toxic payload, monomethyl auristatin F, designed to target EGFR-overexpressing tumor cells. Since long-term glioma cell lines and patient-derived glioma-initiating cell lines appeared to express too little EGFR in vitro to be sensitive to ABT-414, we generated glioma sublines overexpressing EGFR or EGFRvIII to explore the determinants of ABT-414-induced glioma cell death. Overexpression of EGFRvIII induces sensitization to ABT-414 more readily than overexpression of EGFR. There is no bystander killing of cells devoid of EGFR or EGFRvIII expression. Surprisingly, either exposure to EGF or to EGFR tyrosin kinase inhibitors reduce EGFR protein levels and are thus no strategies to promote ABT-414-induced cell killing. Furthermore, glioma cells overexpressing kinase-dead EGFR or EGFRvIII retain binding of mAb 806 and sensitivity to ABT-414, allowing to dissociate EGFR phosphorylation from the emergence of the “active” EGFR conformation required for ABT-414 binding. The combination of EGFR-targeting antibody drug conjugates with EGFR tyrosine kinase inhibitors carries a high risk of failure. Promoting mere EGFR expression rather than phosphorylation should result in glioblastoma cell sensitization to ABT-414 or related agents.

scholarly journals Drug Tolerance to EGFR Tyrosine Kinase Inhibitors in Lung Cancers with EGFR Mutations

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1590
Author(s):  
Kenichi Suda ◽  
Tetsuya Mitsudomi
Keyword(s):  
Lung Cancer ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Molecular Mechanisms ◽  
Kinase Inhibitors ◽  
Drug Tolerance ◽  
Lung Cancers ◽  
Egfr Tyrosine Kinase ◽  
Egfr Tyrosine Kinase Inhibitors ◽  
Egfr Mutated

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) serve as the standard of care for the first-line treatment of patients with lung cancers with EGFR-activating mutations. However, the acquisition of resistance to EGFR TKIs is almost inevitable, with extremely rare exceptions, and drug-tolerant cells (DTCs) that demonstrate reversible drug insensitivity and that survive the early phase of TKI exposure are hypothesized to be an important source of cancer cells that eventually acquire irreversible resistance. Numerous studies on the molecular mechanisms of drug tolerance of EGFR-mutated lung cancers employ lung cancer cell lines as models. Here, we reviewed these studies to generally describe the features, potential origins, and candidate molecular mechanisms of DTCs. The rapid development of an optimal treatment for EGFR-mutated lung cancer will require a better understanding of the underlying molecular mechanisms of the drug insensitivity of DTCs.

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