Early clinical development of epidermal growth factor receptor targeted therapy in breast cancer

Matsuda, Naoko; Lim, Bora; Wang, Xiaoping; Ueno, Naoto T.

doi:10.1080/13543784.2017.1299707

Cited by 45 publications

(33 citation statements)

References 99 publications

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“…The e cacy analysis revealed robust antitumor activities with two cases of PR and a DCR of 70.8% after larotinib mesylate treatment. Notably, tumors expressing wild-type EGFR are often insensitive to EGFR-TKIs [23][24][25][26][27], but in the present study, one case with no EGFR-sensitive mutations achieved and maintained a PR for 19 cycles. Considering the lower IC 50 value calculated in the larotinib mesylate in vitro study, this observation suggests larotinib mesylate may be superior to other TKIs for targeting wild-type EGFR tumors.…”

Section: Discussionmentioning

confidence: 63%

Phase I Trial to Evaluate the Tolerance, Pharmacokinetics and Efficacy of the Broad-Spectrum ErbB Family Inhibitor Larotinib Mesylate in Patients with Advanced Solid Tumors

Liu

Zhu

et al. 2020

Preprint

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Background: The presented phase I, first-in-human study evaluated the tolerance, pharmacokinetics, and preliminary efficacy of larotinib mesylate in patients with advanced solid tumors.Methods: Cancer patients were assigned to receive larotinib mesylate at 50–400 mg dose levels until disease progression or intolerance. Dose-limiting toxicities were assessed during Cycles 0 and 1. Pharmacokinetic evaluations were performed after the first dose and at steady-state. Results: Twenty-five patients with solid tumors were enrolled in the dose-escalation study. No DLTs were observed. Acne-like rash (68.0%), diarrhea (48.0%), paronychia (48.0%), and anemia (48.0%) were the most reported treatment-related adverse events. No clear linear pharmacokinetic characteristic could be drawn, and obvious accumulation was observed. Two patients with non-small cell lung cancer experienced a partial response, and 15 patients had stable disease after treatment. Conclusion: Continuous oral administration of larotinib mesylate at 50–400 mg daily demonstrated a favorable safety profile, and anti-tumor activity was observed in patients with advanced solid tumors.Trial registration: registration no.ChiCTR-OPC-15007153, registered 28 September 2015 at http://www.chictr.org.cn

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Section: Discussionmentioning

confidence: 63%

Phase I Trial to Evaluate the Tolerance, Pharmacokinetics and Efficacy of the Broad-Spectrum ErbB Family Inhibitor Larotinib Mesylate in Patients with Advanced Solid Tumors

Liu

Zhu

et al. 2020

Preprint

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“…It is a kind of glycoprotein receptor with tyrosine kinase activity on the surface of the cell membrane. The mutations in the EGFR lead to EGFR overexpression (known as upregulation) and its high expression can promote the proliferation, adhesion, invasion and metastasis of tumor cells [ 2 ] and is closely associated with non-small cell Lung cancer, breast cancer, gastric cancer, pancreatic cancer, colorectal cancer and other malignant tumors [ 3 , 4 ].…”

Section: Introductionmentioning

confidence: 99%

A cross-talk between integrin β4 and epidermal growth factor receptor induces gefitinib chemoresistance to gastric cancer

Huafeng¹,

Zhang

Yong³

et al. 2018

Cancer Cell Int

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BackgroundGastric cancer presents a major health burden worldwide. Therefore, many molecular targeting agents have been evaluated for treatment of gastric cancer. Gefitinib has shown anticancer activity against gastric cancer which work through inhibiting epidermal growth factor receptor (EGFR). However, the effect of gefitinib is limited due to its resistance. Therefore, understanding the mechanisms of gefitinib resistance is desperately needed to formulate novel strategies against gastric cancer. Here, we analyzed resistance mechanism from the crosstalk between EGFR and integrin β4.MethodsIntegrin β4-expression vector or siRNA were used to analyze the functional effects of integrin β4 on chemoresistance of gastric cancer cells to gefitinib. EGFR and integrin β4 expression, proliferation and apoptosis of gastric cancer cells were assayed by indirect immunofluorescence, western blot, MTT and flow cytometry respectively. EGFR and integrin β4 expression were also assayed on patient samples.ResultsIt was found that the integrin β4 expression was increased in gefitinib-resistant gastric cell line. The upregulated integrin β4 expression was identified to promote gefitinib resistance and proliferation, and inhibit apoptosis, while downregulation of integrin β4 was to inhibit gefitinib resistance and proliferation, and induce apoptosis. Moreover, the overexpression of integrin β4 in SGC7901 cells resulted in the down-regulation of p-EGFR protein levels while down-regulation of integrin β4, significantly resulted in overexpression of p-EGFR. The results of western blot from patients also showed there was obvious negative correlation between p-EGFR and integrin β4 in gastric cancer patients.ConclusionConsidering the above results, it is concluded that the interaction of EGFR and integrin β4 may change the sensitivity of gefitinib treatment.

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“…Epidermal growth factor (EGF) is a crucial factor in mammary gland development [ 16 ] and EGFR-targeted therapy provides some promising effects in patients with triple-negative (estrogen receptor-, progesterone receptor-, and erb-b2 receptor tyrosine kinase 2-negative) breast cancer [ 17 ]. In this study, we aimed to investigate the expression status of CCR1 in breast cancer tissues, the functional relevance of CCR1 in breast cancer metastasis, and the mechanisms underlying the regulation of CCR1 expression in breast cancer cells.…”

Section: Introductionmentioning

confidence: 99%

C-C motif chemokine receptor 1 (CCR1) is a target of the EGF-AKT-mTOR-STAT3 signaling axis in breast cancer cells

Shin

Lee

et al. 2017

Oncotarget

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The CC motif chemokine receptor 1 (CCR1) has been implicated in tumor invasion and metastasis in numerous cancers. However, the detailed mechanism of CCR1 upregulation in metastatic tumor cells is poorly understood. The aim of this study was to clarify the regulatory mechanism underlying transcriptional activation of the CCR1 gene in response to epidermal growth factor (EGF) stimulation in breast cancer cells. CCR1 was highly expressed in human breast invasive ductal carcinoma (IDC) compared to adjacent normal tissues. Upon EGF stimulation, CCR1 expression was upregulated at the transcriptional level. Promoter analysis showed that signal transducer and activator of transcription 3 (STAT3) is necessary for EGF-induced CCR1 promoter activation, and STAT3 silencing abrogated EGF-induced CCR1 transcription. Pharmacological inhibition and short hairpin RNA-mediated knockdown experiments showed that AKT-dependent mammalian target of rapamycin (mTOR) activation was involved in the phosphorylation of serine-727 of STAT3, which in turn stimulated the transcription of the CCR1 gene. In conclusion, the AKT-mTOR-STAT3 signaling axis contributes to EGF-induced CCR1 expression, which promotes invasion and metastasis in breast cancer cells. We propose that the AKT-mTOR-STAT3 axis is a potential therapeutic target for blocking the invasion and metastasis of breast cancers.

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Early clinical development of epidermal growth factor receptor targeted therapy in breast cancer

Cited by 45 publications

References 99 publications

Phase I Trial to Evaluate the Tolerance, Pharmacokinetics and Efficacy of the Broad-Spectrum ErbB Family Inhibitor Larotinib Mesylate in Patients with Advanced Solid Tumors

Phase I Trial to Evaluate the Tolerance, Pharmacokinetics and Efficacy of the Broad-Spectrum ErbB Family Inhibitor Larotinib Mesylate in Patients with Advanced Solid Tumors

A cross-talk between integrin β4 and epidermal growth factor receptor induces gefitinib chemoresistance to gastric cancer

C-C motif chemokine receptor 1 (CCR1) is a target of the EGF-AKT-mTOR-STAT3 signaling axis in breast cancer cells

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