Emerging Approaches to Overcome Acquired Drug Resistance Obstacles to Osimertinib in Non-Small-Cell Lung Cancer
The pyrimidine core-containing compound Osimertinib is the only epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) from the third generation that has been approved by the U.S. Food and Drug Administration to target threonine 790 methionine (T790M) resistance while sparing the wild...
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| Veröffentlicht in: | Journal of medicinal chemistry 2022-01, Vol.65 (2), p.1008-1046 |
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| container_end_page | 1046 |
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| container_issue | 2 |
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| container_title | Journal of medicinal chemistry |
| container_volume | 65 |
| creator | Shaikh, Matin Shinde, Yashodeep Pawara, Rahul Noolvi, Malleshappa Surana, Sanjay Ahmad, Iqrar Patel, Harun |
| description | The pyrimidine core-containing compound Osimertinib is the only epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) from the third generation that has been approved by the U.S. Food and Drug Administration to target threonine 790 methionine (T790M) resistance while sparing the wild-type epidermal growth factor receptor (WT EGFR). It is nearly 200-fold more selective toward the mutant EGFR as compared to the WT EGFR. A tertiary cystein 797 to serine 797 (C797S) mutation in the EGFR kinase domain has hampered Osimertinib treatment in patients with advanced EGFR-mutated non-small-cell lung cancer (NSCLC). This C797S mutation is presumed to induce a tertiary-acquired resistance to all current reversible and irreversible EGFR TKIs. This review summarizes the molecular mechanisms of resistance to Osimertinib as well as different strategies for overcoming the EGFR-dependent and EGFR-independent mechanisms of resistance, new challenges, and a future direction. |
| doi_str_mv | 10.1021/acs.jmedchem.1c00876 |
| format | Article |
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It is nearly 200-fold more selective toward the mutant EGFR as compared to the WT EGFR. A tertiary cystein 797 to serine 797 (C797S) mutation in the EGFR kinase domain has hampered Osimertinib treatment in patients with advanced EGFR-mutated non-small-cell lung cancer (NSCLC). This C797S mutation is presumed to induce a tertiary-acquired resistance to all current reversible and irreversible EGFR TKIs. 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Med. Chem</addtitle><description>The pyrimidine core-containing compound Osimertinib is the only epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) from the third generation that has been approved by the U.S. Food and Drug Administration to target threonine 790 methionine (T790M) resistance while sparing the wild-type epidermal growth factor receptor (WT EGFR). It is nearly 200-fold more selective toward the mutant EGFR as compared to the WT EGFR. A tertiary cystein 797 to serine 797 (C797S) mutation in the EGFR kinase domain has hampered Osimertinib treatment in patients with advanced EGFR-mutated non-small-cell lung cancer (NSCLC). This C797S mutation is presumed to induce a tertiary-acquired resistance to all current reversible and irreversible EGFR TKIs. 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| subjects | Acrylamides - pharmacology Aniline Compounds - pharmacology Animals Carcinoma, Non-Small-Cell Lung - drug therapy Carcinoma, Non-Small-Cell Lung - genetics Carcinoma, Non-Small-Cell Lung - pathology Drug Resistance, Neoplasm ErbB Receptors - genetics Humans Lung Neoplasms - drug therapy Lung Neoplasms - genetics Lung Neoplasms - pathology Mutation Protein Kinase Inhibitors - pharmacology |
| title | Emerging Approaches to Overcome Acquired Drug Resistance Obstacles to Osimertinib in Non-Small-Cell Lung Cancer |
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