Introduction
Third-generation EGFR-TKIs and drug resistance mechanisms
The development of third-generation EGFR-TKIs
Mechanisms of resistance to third-generation EGFR-TKIs
Primary/intrinsic resistance
BIM deletion polymorphism
EGFR exon 20 insertion
Acquired resistance
EGFR-dependent drug resistance mechanisms
Reappearance of an EGFR mutation
C797S mutation
G796R/D mutation
L792 mutation
M766Q mutation
Mutations in exon 18
EGFR L718Q/V
EGFR G724S
Compound mutations
T790M reduction or deletion
EGFR amplification
EGFR-independent resistance mechanisms
Bypass signal pathway activation
Abnormal activation of MET
HER2 amplification
AXL activation
Overexpression of HGF
Fibroblast growth factor receptor (FGFR) signaling
Insulin-like growth factor receptor 1 (IGF1R)
Aurora kinases (AURKs)
Downstream signaling pathway activation
K-RAS mutation
BRAF (v-RAF murine sarcoma viral oncogene homologue B1) mutation
PI3K/AKT/mTOR
STAT3 activation
Loss of PTEN
Hyperactivation of activated Cdc42-associated kinase 1 (ACK1)
c-Myc gene
Other mechanisms
Epithelial–mesenchymal transition (EMT)
miRNAs and EMT
Epigenetic alterations
Oncogene fusion
Cell cycle-related gene abnormalities
Histologic and phenotypic transformation
Immune escape
Strategies for overcoming third-generation EGFR-TKI resistance
Fourth-generation EGFR-TKIs: overcoming the L858R/T790M and C797S resistance mutations
Allosteric inhibitors
Compound (reference) | Structure | Activity | Interaction with EGFR allosteric site |
---|---|---|---|
7, DDC4002 [100] | EGFRL858R/T790M IC50 = 10 nmol/L EGFRL858R/T790M/C797S IC50 = 59 nmol/L | Phe856 | |
8 [100] | EGFRL858R/T790M/C797S IC50 = 19 nmol/L | Phe856 | |
9 [100] | EGFRL858R/T790M/C797S IC50 = 23 nmol/L | Phe856 | |
10 [100] | EGFRL858R/T790M/C797S IC50 = 13 nmol/L | Phe856 | |
EGFRL858R/T790M IC50 = 1 nmol/L EGFRL858R/T790M/C797S IC50 = 5 nmol/L | Phe856 | ||
EGFRL858R/T790M IC50 = 3 nmol/L EGFRL858R/T790M/C797S IC50 = 4 nmol/L | Phe856 |
ATP-competitive inhibitors
Compound (reference) | Structure | Enzymatic activity | Biological activity | DMPK profile |
---|---|---|---|---|
13, JND3229 [102] | EGFRL858R/T790M/C797S IC50 = 5.8 nmol/L | BaF3-EGFRL858R/T790M/C797S IC50 = 510 nmol/L BaF3-EGFRDel19/T790M/C797S IC50 = 320 nmol/L | N/A* | |
14 [103] | EGFRWT IC50 = 16 nmol/L EGFRL858R/T790M/C797S IC50 = 88 nmol/L | A431 GI50 = 3600 nmol/L H1975 GI50 = 140 nmol/L | N/A | |
15 [104] | EGFRL858R/T790M/C797S IC50 = 8 nmol/L | A431 EC50 = 4000 nmol/L H1975 EC50 = 400 nmol/L | N/A | |
EGFRL858R/T790M/C797S IC50 = 630 nmol/L | H1975 IC50 = 1200 nmol/L | Liver microsomes (Human): t1/2 (min) = 66.6, CLint (mL/min/kg) = 20.8 | ||
17 [107] | EGFRWT IC50 > 1000 nmol/L EGFRL858R/T790M/C797S IC50 = 27.5 nmol/L | BaF3-EGFRL858R/T790M/C797S IC50 = 662 nmol/L | T1/2 (rat, minutes) = 8.36, CLint (mL/min/kg) = 297.12 | |
18 [108] | EGFRL858R/T790M/C797S IC50 = 7.2 nmol/L | HCC827 IC50 = 44 nmol/L H1975 IC50 = 400 nmol/L | N/A | |
EGFRL858R/T790M/C797S IC50 = 18 nmol/L | HCC827 IC50 = 0.88 nmol/L H1975 IC50 = 200 nmol/L A549 IC50 = 2910 nmol/L A431 IC50 > 10,000 nmol/L | N/A | ||
20 [111] | EGFRL858R/T790M/C797S IC50 = 8.5 nmol/L | EGFR CTG EC50: HCC827 IC50 < 14 nmol/L H1975 IC50 = 51 ± 19 nmol/L A431 IC50 = 1675 ± 402 nmol/L A549 IC50 = 3700 nmol/L H358 IC50 = 3700 nmol/L | In vivo PK (mice, IP, 20 mg/kg): AUCfree (h∙ng/mL) = 8.6 t1/2 (h) = 1.2 Cmax,free (μmol/L) = 0.012 | |
21 [112] | EGFRL858R/T790M/C797S IC50 = 3.1 nmol/L | H1975 IC50 = 0.12 ± 0.09 μmol/L BaF3-EGFRL858R/T790M/C797S IC50 = 0.29 μmol/L BaF3-EGFR19D/T790M/C797S IC50 = 0.31 μmol/L | N/A | |
22 [113] | EGFRWT IC50 > 1000 nmol/L EGFRL858R/T790M/C797S IC50 = 218.3 nmol/L EGFRDel19/T790M/C797S IC50 = 15.3 nmol/L | H1975 IC50 = 16,180 nmol/L A431 IC50 = 20,480 nmol/L BaF3-EGFRDel19/T790M/C797S IC50 = 8510 nmol/L | N/A | |
23 [114] | EGFRWT IC50 = 430 nmol/L EGFRDel19/T790M/C797S IC50 = 0.2 nmol/L | BaF3-EGFRWT IC50 = 1000 nmol/L BaF3-EGFRDel19 IC50 = 180 nmol/L BaF3-EGFRDel19/T790M IC50 = 99 nmol/L BaF3-EGFRDel19/T790M/C797S IC50 = 63 nmol/L | N/A | |
24 [115] | N/A | Biochemical potency: BaF3 cells IC50 < 100 nmol/L Antiproliferative activity: BaF3 cells IC50 < 100 nmol/L | N/A | |
25 [116] | N/A | Antiproliferative activity: PC-9-EGFRL858R/T790M/C797S IC50 = 595.7 nmol/L PC-9-EGFRDel19/T790M/C797S IC50 = 739.9 nmol/L A549 IC50 = 2861.7 nmol/L BaF3-EGFRWT IC50 = 519.82 nmol/L BaF3-EGFRL858R/T790M/C797S IC50 = 0.16 nmol/L BaF3-EGFRDel19/T790M/C797S IC50 = 0.23 nmol/L | N/A | |
26 [117] | N/A | BaF3-EGFRWT IC50 = 540 nmol/L BaF3-EGFRL858R/T790M/C797S IC50 = 48.2 nmol/L BaF3-EGFRDel19/T790M/C797S IC50 = 12 nmol/L | N/A | |
27 [115] | EGFRWT IC50 = 7.92 nmol/L EGFRL858R/T790M/C797S IC50 = 0.218 nmol/L EGFRDel19/T790M/C797S IC50 = 0.16 nmol/L | Antiproliferative Activity: A431 IC50 = 154 nmol/L BaF3-EGFRDel19/T790M/C797S IC50 = 22 nmol/L | In vivo PK (mice, per os, 15 mg/kg): AUC0-last = 57,037 (nmol/L∙h) t1/2 (h) = 10.0 Plasma (nmol/L), 2 h = 3553 Tumor (nmol/kg), 2 h = 16,667 | |
28 [118] | EGFRWT IC50 = 3.8 nmol/L EGFRL858R/T790M/C797S IC50 = 38.1 nmol/L | BaF3-EGFRL858R/T790M/C797S IC50 < 1000 nmol/L | N/A | |
29, UPR1444 [119] | EGFRWT IC50 = 30 ± 4.8 nmol/L EGFRL858R/T790M/C797S IC50 = 110 ± 33 nmol/L | N/A | N/A |
“Dual-site” inhibitors: occupying both the ATP binding site and the allosteric site
PROTAC technology
Allosteric EGFR degrader
Dual PROTACs
Monoclonal antibodies and ADCs
Combination therapy strategy
Target | Representative compound* | Structure | Reference |
---|---|---|---|
MET | Cabozantinib | ||
MET | Crizotinib | [147] | |
MET | Savolitinib | [148] | |
FGFR | AZD4547 | [149] | |
ALK | Lorlatinib | [150] | |
ALK | Brigatinib | [151] | |
HER2 | JQ1 | [152] | |
HER2 | Trastuzumab-DM1 | [153] | |
BRAF V600E | Encorafenib (LGX818) | [64] | |
AURK B | PF-03814735 |
Target | Representative compound* | Structure | Reference |
---|---|---|---|
MEK | Trametinib | ||
MEK | Selumetinib | ||
MEK | PD0325901 | [155] | |
AKT | Uprosertib (GSK2141795) | [158] | |
AKT | Capivasertib (AZD5363) | [158] | |
AXL | Cabozantinib | [159] | |
AXL | DS-1205b | [160] | |
AXL | Yuanhuadine (YD) | [161] | |
AXL | Bemcentinib (R428) | [162] | |
ACK1 | (R)-9b |
Multitarget inhibitors
Number | Target | Pharmacophores | Structure | Activity |
---|---|---|---|---|
69 [168] | EGFR/FGFR1 | Pyrimidine-2,4-diamines | EGFRL858R/T790M IC50 = 43.1 nmol/L EGFRWT IC50 = 1138.7 nmol/L FGFR1WT IC50 = 17.6 nmol/L H1975 cells IC50 = 336.3 nmol/L | |
70 [169] | EGFR/Src | Pyrimidine-4-amines | K562 cells IC50 = 220 nmol/L A549 cells IC50 = 250 nmol/L EGFR inhibition rate = 33.15% (10 µmol/L) Src inhibition rate = 72.12% (1 µmol/L) | |
71 [170] | EGFR/HER4 | 3-Cyanoquizolines | EGFRL858R IC50 = 419 nmol/L EGFRWT IC50 = 2.4 nmol/L HER4 IC50 = 0.03 nmol/L | |
72 [171] | EGFR/COX2 | 1,3,4-Oxadiazole scaffold | EGFR IC50 = 280 nmol/L COX2 IC50 = 170 nmol/L UO-31 cells IC50 = 5800 nmol/L | |
73 [172] | EGFR/BRAF | Spirobenzo[h]chromene derivatives | EGFR IC50 = 1200 nmol/L BRAF IC50 = 2600 nmol/L A549 cells IC50 = 1780 nmol/L MCF-7 cells IC50 = 4090 nmol/L HT-29 cells IC50 = 4450 nmol/L | |
74 [173] | EGFRT790M/ALK | Pyrimidine-2,4-diamines | ALK IC50 = 18 nmol/L EGFRWT IC50 = 151 nmol/L EGFRT790M IC50 = 2 nmol/L EGFRL858R/T790M IC50 = 4 nmol/L DFCI032 cells IC50 = 170 nmol/L DFCI076 cells IC50 = 820 nmol/L | |
75 [174] | EGFRWT and mutant EGFR/ALK | Pyrimidine-2,4-diamines | EGFRWT IC50 = 108 nmol/L EGFRT790M IC50 = 3.9 nmol/L EGFRL858R/T790M IC50 = 3.6 nmol/L ALKWT IC50 = 9.8 nmol/L ALKR1275Q IC50 = 0.82 nmol/L ALKL1196M IC50 = 0.59 nmol/L ALKF1174L IC50 = 0.92 nmol/L ALKC1156Y IC50 = 1.0 nmol/L H1975 cells GI50 = 15 nmol/L H3112 cells GI50 < 0.3 nmol/L | |
76 [175] | EGFR/ATX | Pyrimidine-4-amines | EGFR IC50 = 24.2 nmol/L ATX IC50 = 29.1 nmol/L A549 cells IC50 = 4960 nmol/L MKN-45 cells IC50 = 3430 nmol/L SGC cells IC50 = 2910 nmol/L CFs cells IC50 = 1490 nmol/L | |
77 [176] | EGFR/AURK A | Pyrimidine-4-amines | AURK A IC50 = 1990 nmol/L EGFR IC50 = 3.76 nmol/L | |
78 [177] | EGFR/IGF1R | Pyrimidine-2-amines | EGFR IC50 = 35.5 nmol/L EGFRT790M IC50 = 66.0 nmol/L IGF1R IC50 = 52.0 nmol/L | |
79 [178] | EGFR/tubulin | Pyrimidine-4-amines | EGFR IC50 = 30 nmol/L Tubulin assembly IC50 = 710 nmol/L HeLa cells IC50 = 1 nmol/L HT-29 cells IC50 = 20 nmol/L Jurkat cells IC50 = 1 nmol/L RS4;11 cells IC50 = 1 nmol/L | |
80 [179] | EGFR/tubulin | Chalcones | EGFR IC50 = 39 nmol/L Tubulin polymerization IC50 = 8840 nmol/L MCF-7 cells IC50 = 1650 nmol/L HCT-116 cells IC50 = 3610 nmol/L | |
81 [180] | EGFR/AKT | Chalcones | A549 cells IC50 = 3820 nmol/L MDA-MB-231 cells IC50 = 5890 nmol/L SKBR3 cells IC50 = 4790 nmol/L | |
82 [181] | EGFR/HDACs | Pyrimidine-2-amines | EGFRWT IC50 = 5700 nmol/L EGFRT790M IC50 = 5000 nmol/L HDACs IC50 = 85 nmol/L A549 cells IC50 = 2190 nmol/L HeLa cells IC50 = 1850 nmol/L MDA-MB-231 cells IC50 = 600 nmol/L MDA-MB-468 cells IC50 = 230 nmol/L | |
83 [182] | EGFR/PDGFR-β | Pyrimidine-2,4-diamines | EGFR Ki IC50 = 170 nmol/L PDGFR-β IC50 = 81 nmol/L | |
84 [183] | EGFR/NF-κB | Quinazolines | EGFR IC50 = 60.1 nmol/L NF-κB IC50 = 300 nmol/L | |
85 [184] | EGFR/c-Met | 1,2,4-Oxadiazole derivate | MDA-MB-231 cells IC50 = 200 nmol/L A459 cells IC50 = 200 nmol/L PC9 cells IC50 = 500 nmol/L H1975 cells IC50 = 300 nmol/L CL68 cells IC50 = 400 nmol/L CL97 cells IC50 = 500 nmol/L | |
86 [185] | EGFRT790M/c-Met | Pyrimidine-2-amines | EGFRT790M IC50 = 97 nmol/L c-Met IC50 = 518 nmol/L | |
87 [186] | EGFR/VEGFR-2 | Pyrimidine-2,4-diamines | EGFR Ki IC50 = 80 nmol/L VEGFR-2 Ki IC50 = 3240 nmol/L NCI-H460 cells GI = 25% (10 µmol/L) | |
88 [187] | EGFR/VEGFR-2 | Quinazolines | EGFR IC50 = 1.0 nmol/L VEGFR-2 IC50 = 79.0 nmol/L HT-29 cells IC50 = 1760 nmol/L MCF7 cells IC50 = 7280 nmol/L | |
89 [188] | EGFR/VEGFR-2 | Quinazolines | EGFR IC50 = 0.69 nmol/L VEGFR-2 IC50 = 67.84 nmol/L | |
90 [59] | EGFR/VEGFR-2 | Quinazolines | EGFR IC50 = 2.0 nmol/L VEGFR-2 IC50 = 103.0 nmol/L A431 cells IC50 = 14.0 nmol/L H1975 cells IC50 = 130.0 nmol/L | |
91 [189] | EGFR/VEGFR-2 | Quinazolines | EGFR IC50 = 20 nmol/L VEGFR-2 IC50 = 50 nmol/L | |
92 [190] | EGFR/HER2 | Quinazolines | EGFR IC50 = 0.69 nmol/L HER2 IC50 = 42.1 nmol/L NCI-H1975 cells IC50 = 12.20 nmol/L HCC827 cells IC50 = 0.31 nmol/L A431 cells IC50 = 1.52 nmol/L MDA-MB-453 cells IC50 = 0.62 nmol/L | |
93 [191] | EGFR/HER2 | Pyrimidine-4-amines | EGFR IC50 = 186 nmol/L VEGFR-2 IC50 = 254 nmol/L | |
94 [192] | EGFR/HER2 | 3-Cyanoquizolines | EGFR IC50 = 597 nmol/L IGF1R IC50 = 908 nmol/L A431 cells IC50 = 1890 nmol/L SKBR3 cells IC50 = 1930 nmol/L | |
EGFR/HER2 | Pyrimidinones | EGFR IC50 = 60 nmol/L HER2 IC50 = 300 nmol/L A549 cells IC50 = 280 nmol/L | ||
96 [196] | EGFR/CSK | Chalcones | EGFR IC50 = 11,120 nmol/L CSK IC50 = 5160 nmol/L | |
97 [197] | EGFR/CAIX | Quinazolines | EGFRWT IC50 = 27.0 nmol/L EGFRT790M IC50 = 9.2 nmol/L hCAII IC50 = 278.2 nmol/L hCAIX IC50 = 115.0 nmol/L A549 cells (hypoxia) IC50 = 2210 nmol/L A549 cells (normoxia) IC50 = 6450 nmol/L HeLa cells IC50 = 1850 nmol/L H1975 cells (hypoxia) IC50 = 1050 nmol/L H1975 cells (normoxia) IC50 = 1940 nmol/L |