Lung Cancer: EGFR Inhibitors with Low Nanomolar Activity against a Therapy‐Resistant L858R/T790M/C797S Mutant

Günther, Marcel; Juchum, Michael; Kelter, Gerhard; Fiebig, H.H.; Laufer, Stefan

doi:10.1002/anie.201603736

Cited by 85 publications

(109 citation statements)

References 18 publications

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“…Unfortunately, more frequently the two resistance mutations occur in cis, a condition that determines resistance to all available EGFR-TKIs, even if combined. In this situation, new generation of irreversible and reversible mutant EGFR inhibitors with strong noncovalent binding properties and with high inhibitory activities against the cysteine-mutated L858R/T790M/ C797S are in development (49).…”

Section: Discussionmentioning

confidence: 99%

Third-generation epidermal growth factor receptor-tyrosine kinase inhibitors in T790M-positive non-small cell lung cancer: review on emerged mechanisms of resistance

Minari

Bordi

Tiseo

2016

Transl. Lung Cancer Res.

155

157

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Section: Discussionmentioning

confidence: 99%

Third-generation epidermal growth factor receptor-tyrosine kinase inhibitors in T790M-positive non-small cell lung cancer: review on emerged mechanisms of resistance

Minari

Bordi

Tiseo

2016

Transl. Lung Cancer Res.

155

157

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“…Gunther and colleagues recently developed a new class of trisubstituted pyridinyl imidazole EGFR inhibitors based on a p38 MAP kinase inhibitor compound [78, 79]. Using molecular modeling, authors synthesized 40 compounds with activity against EGFR mutants and systematically developed metabolically stable noncovalent reversible EGFR inhibitors.…”

Section: Introductionmentioning

confidence: 99%

Third generation EGFR TKIs: current data and future directions

et al. 2018

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Acquired T790 M mutation is the commonest cause of resistance for advanced non-small cell lung cancer (NSCLC) epidermal growth factor receptor (EGFR) mutant patients who had progressed after first line EGFR TKI (tyrosine kinase inhibitor). Several third generation EGFR TKIs which are EGFR mutant selective and wild-type (WT) sparing were developed to treat these patients with T790 M acquired resistant mutation. Osimertinib is one of the third generation EGFR TKIs and is currently the most advanced in clinical development. Unfortunately, despite good initial response, patients who was treated with third generation EGFR TKI would develop acquired resistance and several mechanisms had been identified and the commonest being C797S mutation at exon 20. Several novel treatment options were being developed for patients who had progressed on third generation EGFR TKI but they are still in the early phase of development. Osimertinib under FLAURA study had been shown to have better progression-free survival over first generation EGFR TKI in the first line setting and likely will become the new standard of care.

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“…Third-generation EGFR TKIs have been designed to overcome resistance through covalent binding to the Cys 797 residue of the enzyme, and they are effective against most clinically relevant EGFR mutants while sparing wild-type EGFR. However, the high dependence of three generations of EGFR TKIs on this particular interaction means that additional mutation of Cys 797 results in poor inhibitory activity, which leads to tumor relapse in initially responding patients 34. In future, novel EGFR TKIs should be designed and developed for high inhibitory activities against the cysteine-mutated L858R/T790M/C797S EGFR .…”

Section: Resultsmentioning

confidence: 99%

Three generations of epidermal growth factor receptor tyrosine kinase inhibitors developed to revolutionize the therapy of lung cancer

Zhang

2016

DDDT

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Lung cancer, ~80%–85% of which is non-small-cell lung cancer (NSCLC), is the leading cause of cancer-related mortality worldwide. Sensitizing mutations in epidermal growth factor receptor (EGFR) gene (EGFRm+), such as exon 19 deletions and exon 21 L858R point mutations, are the most important drivers in NSCLC patients. In this respect, small-molecule EGFR tyrosine kinase inhibitors (TKIs) have been designed and developed, which launched the era of targeted, personalized and precise medicine for lung cancer. Patients with EGFRm+ could achieve good responses to the treatment with the first-generation EGFR TKIs, such as erlotinib and gefitinib. However, most patients develop acquired drug resistance mostly driven by the T790M mutation occurring within exon 20. Although the second-generation EGFR TKIs, such as afatinib, dacomitinib and neratinib, demonstrated promising activity against T790M in preclinical models, they have failed to overcome resistance in patients due to dose-limiting toxicity. Recently, the third-generation EGFR TKIs have shown to be effective against cell lines and murine models harboring T790M mutations while sparing wild-type EGFR, which represents a promising breakthrough approach in overcoming T790M-mediated resistance in NSCLC patients. This article provides a comprehensive review of the therapy revolution for NSCLC with three generations of EGFR TKIs.

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Lung Cancer: EGFR Inhibitors with Low Nanomolar Activity against a Therapy‐Resistant L858R/T790M/C797S Mutant

Cited by 85 publications

References 18 publications

Third-generation epidermal growth factor receptor-tyrosine kinase inhibitors in T790M-positive non-small cell lung cancer: review on emerged mechanisms of resistance

Third-generation epidermal growth factor receptor-tyrosine kinase inhibitors in T790M-positive non-small cell lung cancer: review on emerged mechanisms of resistance

Third generation EGFR TKIs: current data and future directions

Three generations of epidermal growth factor receptor tyrosine kinase inhibitors developed to revolutionize the therapy of lung cancer

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