Small-molecule EGFR tyrosine kinase inhibitors for the treatment of cancer

Lee, Chieh Chien; Shiao, Hui Yi; Wang, Wen Chieh; Hsieh, Hsing Pang

doi:10.1517/13543784.2014.928283

Cited by 46 publications

(34 citation statements)

References 94 publications

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“…) and resistance mutation (EGFR T790M ) with structure different from the first-and second-generation EGFR-TKIs (31)(32)(33). Because osimertinib acts at the ATP binding site of the tyrosine kinase domains of EGFR, it is conceivable that osimertinib may inhibit functions of ABC transporters by binding to their ATP-binding sites, which is similar to the mechanism on reversing MDR by several TKIs mentioned above.…”

Section: L858rmentioning

confidence: 97%

Osimertinib (AZD9291) Enhanced the Efficacy of Chemotherapeutic Agents in ABCB1- and ABCG2-Overexpressing Cells In Vitro, In Vivo, and Ex Vivo

Chen

et al. 2016

Molecular Cancer Therapeutics

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The overexpression of ATP-binding cassette (ABC) transporters has been proved to be a major trigger for multidrug resistance (MDR) in certain types of cancer. In our study, we investigated whether osimertinib (AZD9291), a third-generation irreversible tyrosine kinase inhibitor of both activating EGFR mutations and resistance-associated T790M point mutation, could reverse MDR induced by ABCB1 and ABCG2 in vitro, in vivo, and ex vivo. Our results showed that osimertinib significantly increased the sensitivity of ABCB1-and ABCG2-overexpressing cells to their substrate chemotherapeutic agents in vitro and in the model of ABCB1-overexpressing KBv200 cell xenograft in nude mice. Mechanistically, osimertinib increased the intracellular accumulations of doxorubicin (DOX) and Rhodamine 123 (Rho 123) by inhibiting the efflux function of the transporters in ABCB1-or ABCG2-overexpressing cells but not in their parental sensitive cells. Furthermore, osimertinib stimulated the ATPase activity of both ABCB1 and ABCG2 and competed with the [ 125 I] iodoarylazidoprazosin photolabeling bound to ABCB1 or ABCG2, but did not alter the localization and expression of ABCB1 or ABCG2 in mRNA and protein levels nor the phosphorylations of EGFR, AKT, and ERK. Importantly, osimertinib also enhanced the cytotoxicity of DOX and intracellular accumulation of Rho 123 in ABCB1-overexpressing primary leukemia cells. Overall, these findings suggest osimertinib reverses ABCB1-and ABCG2-mediated MDR via inhibiting ABCB1 and ABCG2 from pumping out chemotherapeutic agents and provide possibility for cancer combinational therapy with osimertinib in the clinic.

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Section: L858rmentioning

confidence: 97%

Osimertinib (AZD9291) Enhanced the Efficacy of Chemotherapeutic Agents in ABCB1- and ABCG2-Overexpressing Cells In Vitro, In Vivo, and Ex Vivo

Chen

et al. 2016

Molecular Cancer Therapeutics

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“…43 Tumor diameter was measured with caliper, and the volume calculated with the formula: +/6 £ larger diameter £ (smaller diameter). 2 Mice were killed when the tumor load reached 4,000 mm 3 , and tumor tissues were harvested.…”

Section: In Vivo Tumor Xenograft Studiesmentioning

confidence: 99%

“…1 It has been involved in various malignancies such as non-small cell lung cancers (NSCLC) and colon cancers. [2][3][4][5] EGFR is activated through interaction with its specific ligands, then undergoes a transition from an inactive monomeric form to an active homodimer. 6 Moreover, EGFR may pair with another member of the ErbB receptor family to create an activated heterodimer.…”

Section: Introductionmentioning

confidence: 99%

A human IgG-like bispecific antibody co-targeting epidermal growth factor receptor and the vascular endothelial growth factor receptor 2 for enhanced antitumor activity

Chen

Xie

Acheampong

et al. 2015

Cancer Biology & Therapy

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ABSRTRACTBoth Epidermal Growth Factor Receptor (EGFR) and the Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) play critical roles in tumorigenesis. We hypothesized co-targeting EGFR and VEGFR2 using a bispecific antibody might have significant therapeutic potential. Here,we designed and produced a human IgG-like bispecific antibody (Bi-Ab) based on the variable regions of cetuximab (an anti-EGFR antibody) and mAb-04 (an anti-VEGFR2 antibody developed in our lab) . The Bi-Ab was found to inhibit the proliferation, survival and invasion of cancer cells via ablating phosphorylation of receptor and downstream signaling. In vivo efficacy was demonstrated against established HT-29 and SKOV-3 xenografts grown in nude mice. Studies revealed our Bi-Ab was able to restrain xenografted tumor growth and prolong survival of mice through inhibiting cell proliferation,promoting apoptosis and antiangiogenesis. In contrast to cetuximab or mAb-04 alone, our Bi-Ab exhibits enhanced antitumor activity and has equal or slightly superior activity to their combination (Combi). It shows promise as a therapeutic agent, especially for use against tumors EGFR and/or VEGFR2 over-expressing malignancies.

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“…Lung cancer is the leading cause of cancer-associated death worldwide, and non-small-cell lung cancer (NSCLC) accounts for approximately 85% of all cases [1,2] . Erlotinib (ER) is an orally active, small-molecule tyrosine kinase inhibitor (TKI) and was first approved by the Food and Drug Administration in 2004 for the treatment of locally advanced and metastatic NSCLC after the failure of at least one prior chemotherapy regimen; erlotinib was only approved for EGFR mutations in NSCLC patients [1] .…”

Section: Introductionmentioning

confidence: 99%

“…Erlotinib (ER) is an orally active, small-molecule tyrosine kinase inhibitor (TKI) and was first approved by the Food and Drug Administration in 2004 for the treatment of locally advanced and metastatic NSCLC after the failure of at least one prior chemotherapy regimen; erlotinib was only approved for EGFR mutations in NSCLC patients [1] . Erlotinib is able to reversibly bind to the intracellular tyrosine kinase domain of epidermal growth factor receptor (EGFR) and inhibits EGFR autophosphorylation, which then inhibits cell proliferation.…”

Section: Introductionmentioning

confidence: 99%

Preclinical PK/PD model for combined administration of erlotinib and sunitinib in the treatment of A549 human NSCLC xenograft mice

Ren

Yin

et al. 2016

Acta Pharmacol Sin

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Aim: Combined therapy of EGFR TKI and VEGFR TKI may produce a greater therapeutic benefit and overcome EGFR TKI-induced resistance. However, a previous study shows that a combination of EGFR TKI erlotinib (ER) with VEGFR TKI sunitinib (SU) did not improve the overall survival in patients with non-small-cell lung cancer (NSCLC). In this study we examined the anticancer effect of ER, SU and their combination in the treatment of A549 human NSCLC xenograft mice, and conducted PK/PD modeling and simulations to optimize the dose regimen. Methods: ER (20, 50 mg·kg -1 ·d -1 ) or SU (5, 10, 20 mg·kg -1 ·d -1 ) alone, or their combination were administered to BALB/c nude mice bearing A549 tumors for 22 days. The tumor size and body weight were recorded daily. The experimental data were used to develop PK/PD models describing the quantitative relationship between the plasma concentrations and tumor suppression in different dose regimens. The models were further evaluated and validated, and used to predict the efficacy of different combination regimens and to select the optimal regimen. Results: The in vivo anticancer efficacy of the combination groups was much stronger than that of either drug administered alone. A PK/PD model was developed with a combination index (φ) of 4.4, revealing a strong synergistic effect between ER and SU. The model simulation predicted the tumor growth in different dosage regimens, and showed that the dose of SU played a decisive role in the combination treatment, and suggested that a lower dose of ER (≤5 mg·kg -1 ·d -1 ) and adjusting the dose of SU might yield a better dosage regimen for clinical research. Conclusion: The experimental data and modeling confirm synergistic anticancer effect of ER and SU in the treatment of A549 xenograft mice. The optimal dosage regimen determined by the PK/PD modeling and simulation can be used in future preclinical study and provide a reference for clinical application.

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Small-molecule EGFR tyrosine kinase inhibitors for the treatment of cancer

Cited by 46 publications

References 94 publications

Osimertinib (AZD9291) Enhanced the Efficacy of Chemotherapeutic Agents in ABCB1- and ABCG2-Overexpressing Cells In Vitro, In Vivo, and Ex Vivo

Osimertinib (AZD9291) Enhanced the Efficacy of Chemotherapeutic Agents in ABCB1- and ABCG2-Overexpressing Cells In Vitro, In Vivo, and Ex Vivo

A human IgG-like bispecific antibody co-targeting epidermal growth factor receptor and the vascular endothelial growth factor receptor 2 for enhanced antitumor activity

Preclinical PK/PD model for combined administration of erlotinib and sunitinib in the treatment of A549 human NSCLC xenograft mice

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