Mechanisms of Acquired Resistance and Tolerance to EGFR Targeted Therapy in Non-Small Cell Lung Cancer
Abstract
:Simple Summary
Abstract
1. Introduction
2. Targeted Therapy
3. EGFR Mutations in NSCLC
4. EGFR Targeted Therapy
4.1. First Generation EGFR-TKIs
4.2. Second Generation EGFR-TKIs
4.3. Third Generation EGFR-TKIs
4.4. Fourth Generation EGFR-TKIs
4.5. EGFR Degraders
5. Drug Tolerant Persister States
5.1. Persisters in NSCLC
5.2. Molecular Characteristics of Drug Tolerance in NSCLC
5.2.1. Epigenetic Modifications
5.2.2. Reactivation of EGFR Signaling and Up-Regulation of Other Pathways
5.2.3. Metabolic Reprogramming
5.3. Origin of DTP Cells: Darwinian Selection or Lamarckian Induction?
6. Cellular Barcoding
6.1. Lentiviral Barcodes to Study Resistance to Anti-Cancer Drugs
6.2. Viral-Barcoding Compatible with Single Cell RNA Sequencing
6.3. CRISPR-Barcoding
7. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Class | Drugs | Clinical Trial | Approval | CSF Concentration | EGFR Sensitizing Mutations | EGFR Binding |
---|---|---|---|---|---|---|
First generation | Gefitinib | NCT01203917 | FDA/EMA approved | Low | Del19/L858R | Reversible Competitive |
Erlotinib | NCT00446225 | FDA/EMA approved | ||||
Icotinib | NCT01040780 | Approved in China | ||||
Second generation | Afatinib | NCT01466660 | FDA/EMA approved | Low | Del19/L858R/ T790M | Irreversible Covalent |
Dacomitinib | NCT01774721 | FDA/EMA approved | ||||
Third generation | WZ4002 | NA | Preclinical | NA | Del19/L858R/ T790M | Irreversible Covalent |
Rociletinib | NCT01526928 | Rejected | Low | |||
Osimertinib | NCT02296125 | FDA/EMA approved | High | |||
Lazertinib | NCT03046992 | Approved in South Korea | High | |||
Olmutinib | NCT01588145 | Approved in South Korea * | NA | |||
Avitinib | NCT02330367 | Phase I/II (Active) | Low | |||
Nazartinib | NCT02108964 | Phase I/II (Active) | NA | |||
Mavelertinib | NCT02349633 | Phase I/II (Terminated) | NA | |||
Naquotinib | NCT02588261 | Phase III (Terminated) | NA | |||
Almonertinib | NCT02981108 | Approved in China | Effective in patient with BM | Del19/L858R/ G719X/L861Q/ T790M | ||
Alflutinib | NCT03127449 | Approved in China | ||||
Fourth generation | EAI001 | NA | Preclinical | NA | L858R/T790M/ C797S | Reversible Allosteric |
EAI045 | NA | Preclinical | NA | |||
JBJ-09-063 | NA | Preclinical | NA | |||
BLU945 | NCT04862780 | Phase I/II (Recruiting) | NA | Del19/L858R/ T790M/C797S | Unknown | |
BBT176 | NCT04820023 | Phase I/II (Recruiting) | NA | |||
TQB3804 | NCT04128085 | Phase I (Unknown) | NA |
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Chhouri, H.; Alexandre, D.; Grumolato, L. Mechanisms of Acquired Resistance and Tolerance to EGFR Targeted Therapy in Non-Small Cell Lung Cancer. Cancers 2023, 15, 504. https://doi.org/10.3390/cancers15020504
Chhouri H, Alexandre D, Grumolato L. Mechanisms of Acquired Resistance and Tolerance to EGFR Targeted Therapy in Non-Small Cell Lung Cancer. Cancers. 2023; 15(2):504. https://doi.org/10.3390/cancers15020504
Chicago/Turabian StyleChhouri, Houssein, David Alexandre, and Luca Grumolato. 2023. "Mechanisms of Acquired Resistance and Tolerance to EGFR Targeted Therapy in Non-Small Cell Lung Cancer" Cancers 15, no. 2: 504. https://doi.org/10.3390/cancers15020504