Furmonertinib, a Third-Generation EGFR Tyrosine Kinase Inhibitor, Overcomes Multidrug Resistance through Inhibiting ABCB1 and ABCG2 in Cancer Cells
Abstract
:1. Introduction
2. Results
2.1. Furmonertinib Exhibits Equal Sensitivity in Both Drug-Sensitive and Multidrug-Resistant Cells Overexpressing ABCB1 or ABCG2
2.2. Furmonertinib Reverses Multidrug Resistance Mediated by ABCB1 and ABCG2
2.3. Furmonertinib Enhances Drug-Induced Apoptosis in Multidrug-Resistant Cancer Cells That Overexpress ABCB1 or ABCG2
2.4. Furmonertinib Attenuates the Drug Transport Function of ABCB1 and ABCG2
2.5. Furmonertinib Does Not Alter the protein Expression of ABCB1 and ABCG2 in Multidrug-Resistant Cancer Cells
2.6. Furmonertinib Stimulates the ATPase Activity of ABCB1 and ABCG2
2.7. Docking of Furmonertinib in the Drug-Binding Pockets of ABCB1 and ABCG2
3. Discussion
4. Materials and Methods
4.1. Chemical Reagents and Cell Culture
4.2. Cytotoxicity Assays
4.3. Apoptosis Assays
4.4. Fluorescent Drug Transport Assays
4.5. Immunoblot Analysis
4.6. ATPase Assays
4.7. Docking Analysis
4.8. Quantification and Statistical Analysis
Author Contributions
Funding
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Cell Line | Type | Transporter Overexpressed | IC50 [μM]† (RF‡) |
---|---|---|---|
OVCAR-8 | ovarian | - | 1.77 ± 0.50 (1.0) |
NCI-ADR-RES | ovarian | ABCB1 | 1.55 ± 0.25 (1.1) |
KB-3-1 | epidermal | - | 2.57 ± 0.46 (1.0) |
KB-V1 | epidermal | ABCB1 | 2.77 ± 0.84 (1.1) |
S1 | colon | - | 1.62 ± 0.34 (1.0) |
S1-MI-80 | colon | ABCG2 | 1.96 ± 0.52 (1.2) |
H460 | lung | - | 2.58 ± 0.92 (1.0) |
H460-MX20 | lung | ABCG2 | 4.34 ± 1.73 (1.7) |
pcDNA3.1-HEK293 | - | - | 3.20 ± 1.05 (1.0) |
MDR19-HEK293 | - | ABCB1 | 2.70 ± 0.75 (1.2) |
R482-HEK293 | - | ABCG2 | 3.33 ± 0.78 (1.0) |
Mean IC50† ± SD and (FR‡) | |||
---|---|---|---|
Treatment | Concentration (nM) | OVCAR-8 (Parental) [nM] | NCI-ADR-RES (Resistant) [nM] |
Colchicine | - | 23.90 ± 8.01 (1.0) | 1526.20 ± 339.35 (1.0) |
+ furmonertinib | 50 | 22.75 ± 7.73 (1.1) | 1250.47 ± 246.57 (1.2) |
+ furmonertinib | 100 | 23.57 ± 8.00 (1.0) | 1074.86 ± 218.03 (1.4) |
+ furmonertinib | 200 | 21.34 ± 7.15 (1.1) | 745.88 ± 149.48 * (2.0) |
+ furmonertinib | 500 | 20.22 ± 6.81 (1.2) | 401.24 ± 88.79 ** (3.8) |
+ tariquidar | 1000 | 21.74 ± 7.40 (1.1) | 19.93 ± 6.62 ** (76.6) |
[nM] | [nM] | ||
Vincristine | - | 13.58 ± 3.63 (1.0) | 3686.23 ± 967.13 (1.0) |
+ furmonertinib | 50 | 13.65 ± 3.89 (1.0) | 3167.10 ± 756.17 (1.2) |
+ furmonertinib | 100 | 11.61 ± 3.29 (1.2) | 2301.36 ± 382.26 (1.6) |
+ furmonertinib | 200 | 10.94 ± 2.97 (1.2) | 1406.00 ± 316.48 * (2.6) |
+ furmonertinib | 500 | 11.95 ± 3.72 (1.1) | 353.57 ± 56.65 ** (10.4) |
+ tariquidar | 1000 | 12.75 ± 2.41 (1.1) | 20.53 ± 4.91 ** (179.6) |
[nM] | [nM] | ||
Paclitaxel | - | 4.64 ± 1.39 (1.0) | 6028.87 ± 1361.30 (1.0) |
+ furmonertinib | 50 | 5.56 ± 1.72 (0.8) | 2112.46 ± 258.38 ** (2.9) |
+ furmonertinib | 100 | 4.81 ± 1.38 (1.0) | 1517.14 ± 175.31 ** (4.0) |
+ furmonertinib | 200 | 4.74 ± 1.41 (1.0) | 1151.65 ± 132.65 ** (5.2) |
+ furmonertinib | 500 | 4.38 ± 1.29 (1.1) | 440.67 ± 69.20 ** (13.7) |
+ tariquidar | 1000 | 4.91 ± 1.71 (0.9) | 6.81 ± 0.86 ** (885.3) |
Treatment | Concentration (nM) | KB-3-1 (parental) [nM] | KB-V1 (resistant) [nM] |
Colchicine | - | 9.03 ± 3.56 (1.0) | 1122.05 ± 88.87 (1.0) |
+ furmonertinib | 50 | 8.67 ± 3.53 (1.0) | 1001.80 ± 67.14 (1.1) |
+ furmonertinib | 100 | 8.67 ± 3.56 (1.0) | 883.44 ± 76.84 * (1.3) |
+ furmonertinib | 200 | 7.99 ± 3.04 (1.1) | 709.68 ± 72.67 ** (1.6) |
+ furmonertinib | 500 | 7.93 ± 2.91 (1.1) | 723.82 ± 117.88 ** (1.6) |
+ tariquidar | 1000 | 9.25 ± 3.58 (1.0) | 13.90 ± 4.76 *** (80.7) |
[nM] | [nM] | ||
Vincristine | - | 0.61 ± 0.17 (1.0) | 1326.18 ± 152.98 (1.0) |
+ furmonertinib | 50 | 0.70 ± 0.17 (0.9) | 1454.11 ± 178.66 (0.9) |
+ furmonertinib | 100 | 0.85 ± 0.20 (0.7) | 718.77 ± 86.65 ** (1.8) |
+ furmonertinib | 200 | 0.93 ± 0.19 (0.7) | 341.47 ± 66.82 *** (3.9) |
+ furmonertinib | 500 | 0.70 ± 0.17 (0.9) | 58.79 ± 7.72 *** (22.6) |
+ tariquidar | 1000 | 0.84 ± 0.21 (0.7) | 2.46 ± 0.39 *** (539.1) |
[nM] | [nM] | ||
Paclitaxel | - | 2.20 ± 0.72 (1.0) | 4853.95 ± 956.95 (1.0) |
+ furmonertinib | 50 | 2.50 ± 0.80 (0.9) | 4135.80 ± 636.52 (1.2) |
+ furmonertinib | 100 | 2.28 ± 0.71 (1.0) | 2559.00 ± 224.96 * (1.9) |
+ furmonertinib | 200 | 2.27 ± 0.67 (1.0) | 856.05 ± 125.12 ** (5.7) |
+ furmonertinib | 500 | 1.94 ± 0.39 (1.1) | 484.82 ± 35.84 ** (10.0) |
+ tariquidar | 1000 | 2.82 ± 0.95 (0.8) | 2.01 ± 0.44 *** (2414.9) |
Treatment | Concentration (nM) | pcDNA3.1-HEK293 (parental) [nM] | MDR19-HEK293 (resistant) [nM] |
Colchicine | - | 10.80 ± 3.65 (1.0) | 252.60 ± 46.84 (1.0) |
+ furmonertinib | 50 | 13.46 ± 3.75 (0.8) | 197.78 ± 28.41 (1.3) |
+ furmonertinib | 100 | 12.23 ± 3.30 (0.9) | 199.57 ± 29.25 (1.3) |
+ furmonertinib | 200 | 11.70 ± 3.25 (0.9) | 113.33 ± 15.25 ** (2.2) |
+ furmonertinib | 500 | 13.70 ± 3.28 (0.8) | 85.80 ± 12.09 ** (2.9) |
+ tariquidar | 1000 | 10.48 ± 3.41 (1.0) | 8.56 ± 2.86 *** (29.5) |
[nM] | [nM] | ||
Vincristine | - | 4.11 ± 0.88 (1.0) | 622.69 ± 70.96 (1.0) |
+ furmonertinib | 50 | 3.55 ± 0.56 (1.2) | 448.77 ± 48.45 * (1.4) |
+ furmonertinib | 100 | 2.91 ± 0.57 (1.4) | 257.92 ± 40.13 ** (2.4) |
+ furmonertinib | 200 | 3.12 ± 0.67 (1.3) | 145.20 ± 29.42 *** (4.3) |
+ furmonertinib | 500 | 3.41 ± 0.70 (1.2) | 44.35 ± 10.68 *** (14.0) |
+ tariquidar | 1000 | 3.14 ± 0.72 (1.3) | 3.95 ± 0.68 *** (157.6) |
[nM] | [nM] | ||
Paclitaxel | - | 2.14 ± 0.43 (1.0) | 847.15 ± 90.57 (1.0) |
+ furmonertinib | 50 | 1.71 ± 0.23 (1.3) | 1094.67 ± 104.23 * (0.8) |
+ furmonertinib | 100 | 2.23 ± 0.32 (1.0) | 509.01 ± 67.50 ** (1.7) |
+ furmonertinib | 200 | 1.98 ± 0.26 (1.1) | 335.46 ± 52.97 ** (2.5) |
+ furmonertinib | 500 | 2.04 ± 0.25 (1.0) | 98.04 ± 15.98 *** (8.6) |
+ tariquidar | 1000 | 1.64 ± 0.37 (1.3) | 2.57 ± 0.27 *** (329.6) |
Mean IC50† ± SD and (FR‡) | |||
---|---|---|---|
Treatment | Concentration (nM) | S1 (Parental) [nM] | S1-MI-80 (Resistant) [nM] |
Mitoxantrone | - | 1.89 ± 0.26 (1.0) | 85.12 ± 18.43 (1.0) |
+ furmonertinib | 50 | 2.48 ± 0.42 (0.8) | 16.66 ± 2.83 ** (5.1) |
+ furmonertinib | 100 | 2.03 ± 0.25 (0.9) | 8.12 ± 1.13 ** (10.5) |
+ furmonertinib | 200 | 1.51 ± 0.15 (1.3) | 2.56 ± 0.46 ** (33.3) |
+ furmonertinib | 500 | 1.09 ± 0.11 ** (1.7) | 0.42 ± 0.11 ** (202.7) |
+ Ko143 | 1000 | 1.58 ± 0.21 (1.2) | 0.64 ± 0.15 ** (133.0) |
[nM] | [nM] | ||
SN-38 | - | 13.88 ± 1.14 (1.0) | 2472.70 ± 432.26 (1.0) |
+ furmonertinib | 50 | 14.83 ± 3.33 (0.9) | 1170.35 ± 190.54 ** (2.1) |
+ furmonertinib | 100 | 15.04 ± 3.52 (0.9) | 264.30 ± 36.21 *** (9.4) |
+ furmonertinib | 200 | 12.15 ± 3.08 (1.1) | 69.18 ± 8.10 *** (35.7) |
+ furmonertinib | 500 | 10.77 ± 3.45 (1.3) | 32.95 ± 3.23 *** (75.04) |
+ Ko143 | 1000 | 14.23 ± 1.05 (1.0) | 25.26 ± 3.20 *** (97.9) |
[nM] | [μM] | ||
Topotecan | - | 80.77 ± 13.38 (1.0) | 9.60 ± 0.89 (1.0) |
+ furmonertinib | 50 | 72.60 ± 11.15 (1.1) | 2.42 ± 0.35 *** (4.0) |
+ furmonertinib | 100 | 73.24 ± 11.61 (1.1) | 1.68 ± 0.20 *** (5.7) |
+ furmonertinib | 200 | 69.80 ± 11.95 (1.2) | 0.30 ± 0.04 *** (32.0) |
+ furmonertinib | 500 | 69.18 ± 10.53 (1.2) | 0.12 ± 0.02 *** (80.0) |
+ Ko143 | 1000 | 70.82 ± 12.42 (1.1) | 0.14 ± 0.02 *** (68.6) |
Treatment | Concentration (nM) | H460 (parental) [nM] | H460-MX20 (resistant) [nM] |
Mitoxantrone | - | 2.87 ± 0.37 (1.0) | 173.44 ± 31.97 (1.0) |
+ furmonertinib | 50 | 1.50 ± 0.19 ** (1.9) | 53.51 ± 11.11 ** (3.2) |
+ furmonertinib | 100 | 0.89 ± 0.08 *** (3.2) | 29.30 ± 5.41 ** (5.9) |
+ furmonertinib | 200 | 1.16 ± 0.15 ** (2.5) | 18.75 ± 3.07 ** (9.3) |
+ furmonertinib | 500 | 0.80 ± 0.05 *** (3.6) | 13.22 ± 2.15 *** (13.1) |
+ Ko143 | 1000 | 1.67 ± 0.37 * (1.7) | 14.68 ± 1.93 ** (11.8) |
[nM] | [nM] | ||
SN-38 | - | 7.41 ± 0.70 (1.0) | 122.85 ± 23.43 (1.0) |
+ furmonertinib | 50 | 6.21 ± 1.61 (1.2) | 51.19 ± 11.39 ** (2.4) |
+ furmonertinib | 100 | 4.35 ± 0.80 ** (1.7) | 28.49 ± 6.16 ** (4.3) |
+ furmonertinib | 200 | 4.09 ± 0.71 ** (1.8) | 19.99 ± 4.00 ** (6.1) |
+ furmonertinib | 500 | 2.78 ± 0.38 *** (2.7) | 11.25 ± 2.27 ** (10.9) |
+ Ko143 | 1000 | 1.71 ± 0.21 *** (4.3) | 4.00 ± 0.97 *** (30.7) |
[nM] | [nM] | ||
Topotecan | - | 37.38 ± 6.31 (1.0) | 306.91 ± 93.67 (1.0) |
+ furmonertinib | 50 | 24.39 ± 3.44 * (1.5) | 145.73 ± 38.23 (2.1) |
+ furmonertinib | 100 | 19.68 ± 3.37 * (1.9) | 96.44 ± 27.03 * (3.2) |
+ furmonertinib | 200 | 20.86 ± 3.27 * (1.8) | 56.66 ± 14.52 * (5.4) |
+ furmonertinib | 500 | 12.55 ± 1.67 ** (3.0) | 45.34 ± 14.13 ** (6.8) |
+ Ko143 | 1000 | 18.01 ± 2.58 ** (2.1) | 14.23 ± 2.38 ** (21.6) |
Treatment | Concentration (nM) | pcDNA3.1-HEK293 (parental) [nM] | R482-HEK293 (resistant) [nM] |
Mitoxantrone | - | 5.42 ± 0.60 (1.0) | 336.14 ± 46.31 (1.0) |
+ furmonertinib | 50 | 4.38 ± 0.51 (1.2) | 19.37 ± 2.08 *** (17.4) |
+ furmonertinib | 100 | 3.31 ± 0.41 ** (1.6) | 12.12 ± 1.42 *** (27.7) |
+ furmonertinib | 200 | 3.00 ± 0.31 ** (1.8) | 6.24 ± 0.92 *** (53.9) |
+ furmonertinib | 500 | 2.88 ± 0.38 ** (1.9) | 5.82 ± 0.78 *** (57.8) |
+ Ko143 | 1000 | 5.89 ± 0.54 (0.9) | 7.74 ± 0.88 *** (43.4) |
[nM] | [nM] | ||
SN-38 | - | 8.66 ± 2.00 (1.0) | 635.73 ± 68.95 (1.0) |
+ furmonertinib | 50 | 13.04 ± 1.96 (0.7) | 317.93 ± 26.51 ** (2.0) |
+ furmonertinib | 100 | 11.85 ± 1.69 (0.7) | 160.41 ± 8.61 *** (4.0) |
+ furmonertinib | 200 | 11.81 ± 1.75 (0.7) | 96.41 ± 10.31 *** (6.6) |
+ furmonertinib | 500 | 10.28 ± 1.49 (0.8) | 48.84 ± 1.89 *** (13.0) |
+ Ko143 | 1000 | 7.25 ± 1.67 (1.2) | 13.50 ± 1.84 *** (47.1) |
[nM] | [nM] | ||
Topotecan | - | 99.39 ± 19.85 (1.0) | 1579.30 ± 122.74 (1.0) |
+ furmonertinib | 50 | 99.82 ± 18.05 (1.0) | 541.02 ± 36.31 *** (2.9) |
+ furmonertinib | 100 | 92.00 ± 14.52 (1.1) | 400.12 ± 27.23 *** (3.9) |
+ furmonertinib | 200 | 97.31 ± 16.46 (1.0) | 230.62 ± 19.11 *** (6.8) |
+ furmonertinib | 500 | 118.90 ± 18.70 (0.8) | 116.67 ± 10.91 *** (13.5) |
+ Ko143 | 1000 | 92.57 ± 18.20 (1.1) | 154.15 ± 19.24 *** (10.2) |
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Wu, C.-P.; Li, Y.-C.; Murakami, M.; Hsiao, S.-H.; Lee, Y.-C.; Huang, Y.-H.; Chang, Y.-T.; Hung, T.-H.; Wu, Y.-S.; Ambudkar, S.V. Furmonertinib, a Third-Generation EGFR Tyrosine Kinase Inhibitor, Overcomes Multidrug Resistance through Inhibiting ABCB1 and ABCG2 in Cancer Cells. Int. J. Mol. Sci. 2023, 24, 13972. https://doi.org/10.3390/ijms241813972
Wu C-P, Li Y-C, Murakami M, Hsiao S-H, Lee Y-C, Huang Y-H, Chang Y-T, Hung T-H, Wu Y-S, Ambudkar SV. Furmonertinib, a Third-Generation EGFR Tyrosine Kinase Inhibitor, Overcomes Multidrug Resistance through Inhibiting ABCB1 and ABCG2 in Cancer Cells. International Journal of Molecular Sciences. 2023; 24(18):13972. https://doi.org/10.3390/ijms241813972
Chicago/Turabian StyleWu, Chung-Pu, Yen-Ching Li, Megumi Murakami, Sung-Han Hsiao, Yun-Chieh Lee, Yang-Hui Huang, Yu-Tzu Chang, Tai-Ho Hung, Yu-Shan Wu, and Suresh V. Ambudkar. 2023. "Furmonertinib, a Third-Generation EGFR Tyrosine Kinase Inhibitor, Overcomes Multidrug Resistance through Inhibiting ABCB1 and ABCG2 in Cancer Cells" International Journal of Molecular Sciences 24, no. 18: 13972. https://doi.org/10.3390/ijms241813972