|Table of Contents|

Research progress on the mechanism of drug resistance of the third generation EGFR-TKIs and the fourth generation EGFR inhibitors

Journal Of Modern Oncology[ISSN:1672-4992/CN:61-1415/R]

2023 13
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Research progress on the mechanism of drug resistance of the third generation EGFR-TKIs and the fourth generation EGFR inhibitors
CHEN YuanLIU Lingshuang
Longhua Hospital Affiliated to Shanghai University of Chinese Medicine,Shanghai 200032,China.
EGFR-TKIsoxitinibnon-small cell lung cancer
The discovery of EGFR gene mutations detected in up to 50% of lung adenocarcinoma patients and the development of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have revolutionized the treatment of lung cancer.At present,EGFR-TKIs have been developed into three generations.Third generation EGFR-TKIs that overcome first/second generation resistance show a significant advantage in patient survival.However,as with other targeted therapies,new EGFR mutations,as well as other resistance mechanisms,emerge quickly after treatment,posing a significant barrier to cancer therapies aimed at overcoming this chemical resistance.In this review,we summarize the molecular mechanisms of drug resistance to third generation EGFR inhibitors and ongoing efforts to address and overcome this chemical resistance.The status quo of the fourth generation of EGFR-TKIs is also discussed.These inhibitors are of great value in overcoming resistance to the third generation of EGFR-TKIs and seem to have greater therapeutic benefits in clinical practice.


[1] KUMAR A,PETRI ET,HALMOS B,et al.Structure and clinical relevance of the epidermal growth factor receptor in human cancer[J].J Clin Oncol,2008,26(10):1742-1751.
[2] MAEMONDO M,INOUE A,KOBAYASHI K,et al.Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR[J].N Engl J Med,2010,362(25):2380-2388.
[3] GUARDIOLA S,VARESE M,SANCHEZ-NAVARRO M,et al.A third shot at EGFR:New opportunities in cancer therapy[J].Trends Pharmacol Sci,2019,40(12):941-955.
[4] PORCELLI L,GIOVANNETTI E,ASSARAF YG,et al.The EGFR pathway regulates BCRP expression in NSCLC cells:role of erlotinib[J].Curr Drug Targets,2014,15(14):1322-1330.
[5] ASSARAF YG,BROZOVIC A,GONCALVES AC,et al.The multi-factorial nature of clinical multidrug resistance in cancer[J].Drug Resist Updat,2019,46:100645.
[6] BAR-ZEEV M,LIVNEY YD,ASSARAF YG.Targeted nanomedicine for cancer therapeutics:Towards precision medicine overcoming drug resistance[J].Drug Resist Updat,2017,31:15-30.
[7] GONEN N,ASSARAF YG.Antifolates in cancer therapy:structure,activity and mechanisms of drug resistance[J].Drug Resist Updat,2012,15(4):183-210.
[8] LEONETTI A,ASSARAF YG,VELTSISTA PD,et al.MicroRNAs as a drug resistance mechanism to targeted therapies in EGFR-mutated NSCLC:Current implications and future directions[J].Drug Resist Updat,2019,42:1-11.
[9] LEONETTI A,WEVER B,MAZZASCHI G,et al.Molecular basis and rationale for combining immune checkpoint inhibitors with chemotherapy in non-small cell lung cancer[J].Drug Resist Updat,2019,46:100644.
[10] LEPELTIER E,RIJO P,RIZZOLIO F,et al.Nanomedicine to target multidrug resistant tumors[J].Drug Resist Updat,2020,52:100704.
[11] MOSCA L,ILARI A,FAZI F,et al.Taxanes in cancer treatment:Activity,chemoresistance and its overcoming[J].Drug Resist Updat,2021,54:100742.
[12] ZHITOMIRSKY B,ASSARAF YG.Lysosomes as mediators of drug resistance in cancer[J].Drug Resist Updat,2016,24:23-33.
[13] MALAPELLE U,RICCIUTI B,BAGLIVO S,et al.Osimertinib[J].Recent Results Cancer Res,2018,211:257-276.
[14] NAGANO T,TACHIHARA M,NISHIMURA Y.Mechanism of resistance to epidermal growth factor receptor-tyrosine kinase inhibitors and a potential treatment strategy[J].Cells,2018,7(11):212.
[15] OXNARD GR,HU Y,MILEHAM KF,et al.Assessment of resistance mechanisms and clinical implications in patients with EGFR T790M-positive lung cancer and acquired resistance to osimertinib[J].JAMA Oncol,2018,4(11):1527-1534.
[16] MEHLMAN C,CADRANEL J,ROUSSEAU-BUSSAC G,et al.Resistance mechanisms to osimertinib in EGFR-mutated advanced non-small-cell lung cancer:A multicentric retrospective French study[J].Lung Cancer,2019,137:149-156.
[17] ETTINGER DS,WOOD DE,AISNER DL,et al.NCCN guidelines insights:non-small cell lung cancer,version 2.2021[J].J Natl Compr Canc Netw,2021,19(3):254-266.
[18] WALIA M,SINGHAL MK,KAMLE MS.Ideal sequencing in stage IV epidermal growth factor receptor mutant non-small-cell lung cancer[J].Indian Journal of Cancer,2022,59:S80-S89.
[19] TAN CS,KUMARAKULASINGHE NB,HUANG YQ,et al.Third generation EGFR TKIs:current data and future directions[J].Mol Cancer,2018,17(1):29.
[20] JIA Y,YUN CH,PARK E,et al.Overcoming EGFR(T790M) and EGFR(C797S) resistance with mutant-selective allosteric inhibitors[J].Nature,2016,534(7605):129-132.
[21] YAN XE,AYAZ P,ZHU SJ,et al.Structural basis of AZD9291 selectivity for EGFR T790M[J].J Med Chem,2020,63(15):8502-8511.
[22] THRESS KS,PAWELETZ CP,FELIP E,et al.Acquired EGFR C797S mutation mediates resistance to AZD9291 in non-small cell lung cancer harboring EGFR T790M[J].Nat Med,2015,21(6):560-562.
[23] YU HA,TIAN SK,DRILON AE,et al.Acquired resistance of EGFR-mutant lung cancer to a T790M-specific EGFR inhibitor:emergence of a third mutation (C797S) in the EGFR tyrosine kinase domain[J].JAMA Oncol,2015,1(7):982-984.
[24] ARULANANDA S,DO H,MUSAFER A,et al.Combination osimertinib and gefitinib in C797S and T790M EGFR-mutated non-small cell lung cancer[J].J Thorac Oncol,2017,12(11):1728-1732.
[25] ZHOU Z,ZHAO Y,SHEN S,et al.Durable clinical response of lung adenocarcinoma harboring EGFR 19Del/T790M/in trans-C797S to combination therapy of first- and third-generation EGFR tyrosine kinase inhibitors[J].J Thorac Oncol,2019,14(8):e157-e159.
[26] YANG Z,YANG N,OU Q,et al.Investigating novel resistance mechanisms to third-generation EGFR tyrosine kinase inhibitor osimertinib in non-small cell lung cancer patients[J].Clinical Cancer Research,2018,24(13):3097-3107.
[27] STARRETT JH,GUERNET AA,CUOMO ME,et al.Drug sensitivity and allele specificity of first-line osimertinib resistance EGFR mutations[J].Cancer Res,2020,80(10):2017-2030.
[28] CHO JH,LIM SH,AN HJ,et al.Osimertinib for patients with non-small-cell lung cancer harboring uncommon EGFR mutations:A multicenter,open-label,phase II trial (KCSG-LU15-09)[J].J Clin Oncol,2020,38(5):488-495.
[29] FASSUNKE J,MLLER F,KEUL M,et al.Overcoming EGFRG724S-mediated osimertinib resistance through unique binding characteristics of second-generation EGFR inhibitors[J].Nature Communications,2018,9(1):4655.
[30] BROWN BP,ZHANG YK,WESTOVER D,et al.On-target resistance to the mutant-selective EGFR inhibitor osimertinib can develop in an allele-specific manner dependent on the original EGFR-activating mutation[J].Clin Cancer Res,2019,25(11):3341-3351.
[31] ERCAN D,CHOI HG,YUN CH,et al.EGFR mutations and resistance to irreversible pyrimidine-based EGFR inhibitors[J].Clin Cancer Res,2015,21(17):3913-3923.
[32] ASSADOLLAHI V,RASHIDIEH B,ALASVAND M,et al.Interaction and molecular dynamics simulation study of Osimertinib (AstraZeneca 9291) anticancer drug with the EGFR kinase domain in native protein and mutated L844V and C797S[J].J Cell Biochem,2019,120(8):13046-13055.
[33] CHEN L,FU W,ZHENG L,et al.Recent progress of small-molecule epidermal growth factor receptor (EGFR) inhibitors against C797S resistance in non-small-cell lung cancer[J].J Med Chem,2018,61(10):4290-4300.
[34] LU X,YU L,ZHANG Z,et al.Targeting EGFR(L858R/T790M) and EGFR(L858R/T790M/C797S) resistance mutations in NSCLC:Current developments in medicinal chemistry[J].Med Res Rev,2018,38(5):1550-1581.
[35] LU X,SMAILL JB,DING K.Medicinal chemistry strategies for the development of kinase inhibitors targeting point mutations[J].J Med Chem,2020,63(19):10726-10741.
[36] HE J,ZHOU ZH,SUN X,et al.The new opportunities in medicinal chemistry of fourth-generation EGFR inhibitors to overcome C797S mutation[J].European Journal of Medicinal Chemistry,2021,210:112995.
[37] LU S,QIU Y,NI D,et al.Emergence of allosteric drug-resistance mutations:new challenges for allosteric drug discovery[J].Drug Discov Today,2020,25(1):177-184.
[38] DONG RF,ZHU ML,LIU MM,et al.EGFR mutation mediates resistance to EGFR tyrosine kinase inhibitors in NSCLC:From molecular mechanisms to clinical research[J].Pharmacol Res,2021,167:105583.
[39] ENGEL J,RICHTERS A,GETLIK M,et al.Targeting drug resistance in EGFR with covalent inhibitors:a structure-based design approach[J].J Med Chem,2015,58(17):6844-6863.
[40] WU X,GUO Q,LI Q,et al.Molecular mechanism study of EGFR allosteric inhibitors using molecular dynamics simulations and free energy calculations[J].Journal of Biomolecular Structure and Dynamics,2021,2021:1-10.
[41] KANNAN S,VENKATACHALAM G,LIM HH,et al.Conformational landscape of the epidermal growth factor receptor kinase reveals a mutant specific allosteric pocket[J].Chem Sci,2018,9(23):5212-5222.
[42] CHO J,CHEN L,SANGJI N,et al.Cetuximab response of lung cancer-derived EGF receptor mutants is associated with asymmetric dimerization[J].Cancer Res,2013,73(22):6770-6779.
[43] LI D,SHIMAMURA T,JI H,et al.Bronchial and peripheral murine lung carcinomas induced by T790M-L858R mutant EGFR respond to HKI-272 and rapamycin combination therapy[J].Cancer Cell,2007,12(1):81-93.
[44] LI MM,XU Y,GUO JJ.Insights into the negative regulation of EGFR upon the binding of an allosteric inhibitor[J].Chemical Biology & Drug Design,2022,99(4):650-661.
[45] TO C,JANG J,CHEN T,et al.Single and dual targeting of mutant EGFR with an allosteric inhibitor[J].Cancer Discov,2019,9(7):926-943.
[46] QIU Y,YIN X,LI X,et al.Untangling dual-targeting therapeutic mechanism of epidermal growth factor receptor (EGFR) based on reversed allosteric communication[J].Pharmaceutics,2021,13(5):747.
[47] JIA Y,YUN CH,PARK E,et al.Overcoming EGFR(T790M) and EGFR(C797S) resistance with mutant-selective allosteric inhibitors[J].Nature,2016,534(7605):129-132.
[48] KASHIMA K,KAWAUCHI H,TANIMURA H,et al.CH7233163 overcomes osimertinib-resistant EGFR-Del19/T790M/C797S mutation[J].Molecular Cancer Therapeutics,2020,19(11):2288-2297.
[49] LIM SM,PARK C,ZHANG Z,et al.BLU-945,a fourth-generation,potent and highly selective epidermal growth factor receptor tyrosine kinase inhibitor with intracranial activity,demonstrates robust in vivo anti-tumor activity in models of osimertinib-resistant non-small cell lung cancer [J/OL].[2021-04-06].https://www.blueprintmedicines.com/wp-content/uploads/2021/04/Blueprint-Medicines-AACR-2021-BLU-945-Lung-Cancer-Poster.pdf.
[50] DU X,YANG B,AN Q,et al.Acquired resistance to third-generation EGFR-TKIs and emerging next-generation EGFR inhibitors[J].Innovation (N Y),2021,2(2):100103.
[51] DONG R,ZHU M,LIU M,et al.EGFR mutation mediates resistance to EGFR tyrosine kinase inhibitors in NSCLC:From molecular mechanisms to clinical research[J].Pharmacological Research,2021,167:105583.


Last Update: 2023-05-31