Survival of Cancer Cells Is Maintained by EGFR Independent of Its Kinase Activity

Zhang, Weihua; Tsan, Rachel; Huang, Wei-Chien; Wu, Qiuyu; Chiu, Chao Hua; Fidler, Isaiah J.; Hung, Mien‐Chie

doi:10.1016/j.ccr.2008.03.015

Cited by 434 publications

(444 citation statements)

References 44 publications

(43 reference statements)

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“…In contrast, gefitinib-resistant cells exhibited no measurable changes in FDG uptake, either in cell culture or in vivo (Su et al, 2006). Recent findings (Weihua et al, 2008) have suggested that overexpression of EGFR is associated with tumour cell proliferation and survival, and this was attributed to maintaining the intracellular glucose level through interaction and stabilisation of the sodium/glucose cotransporter 1 (SGLT1). This suggests that inhibition of the EGFR kinase activity for cancer therapy may not provide the expected efficacy (Weihua et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

Epidermal growth factor receptor expression escapes androgen regulation in prostate cancer: a potential molecular switch for tumour growth

2009

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Androgen deprivation therapy reduces prostate cancer (PCa) tumour growth; however, disease relapse often ensues independently of androgen stimulation, producing androgen-refractory tumours with increased invasion, proliferation, and malignancy. Androgens downregulate epidermal growth factor receptor (EGFR) in normal prostate but not in PCa. Thus, loss of EGFR regulation and altered signalling may, in part, explain the transition of prostate tumours from androgen dependent to androgen independent. Studies in animal models, PCa cell lines, and tumour specimens suggest that androgens modulate prostate growth and function through mechanisms that involve 'cross-talk' between androgen receptor (AR) and growth factor receptor signalling pathways. The objective of this review is to discuss the paradoxical relationship between androgen regulation of EGFR in normal prostate and PCa. We reviewed the literature from mid-1980s through 2009 to assess the relationship between androgens and EGFR function in modulating the growth of normal prostate and PCa. Loss of androgen regulation of EGFR in PCa may be responsible for increased tumour growth, invasion, and metastasis, with important implications on the clinical management of PCa. We advance the hypothesis that a molecular switch, responsible for downregulating EGFR expression by androgens in the normal prostate, is either lost or modified in PCa.

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Section: Discussionmentioning

confidence: 99%

Epidermal growth factor receptor expression escapes androgen regulation in prostate cancer: a potential molecular switch for tumour growth

2009

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“…The strategy of dominant-negative mutants can only abrogate one function of survivin at one time, whereas siRNA can interrupt all the functions of survivin simultaneously and this may reinforce the inhibitory effect on the functions of survivin. 26 To date, several survivin isoforms have been reported, but the detailed biological function and mechanism are still not elucidated clearly. Given the fact that survivin is overexpressed in HCC tissue, we concluded that all survivin isoforms existing in HCC are promising targets for the treatment.…”

Section: Discussionmentioning

confidence: 99%

Survivin knockdown by short hairpin RNA abrogates the growth of human hepatocellular carcinoma xenografts in nude mice

Zhang

Zheng

et al. 2009

Cancer Gene Ther

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Abnormal high activation of survivin is involved in carcinogenesis of various types of cancer. Survivin has been shown to promote cell proliferation in human hepatocellular carcinoma (HCC). Survivin-targeting approaches have become a promising strategy for treating HCC. Here, we used a reporter system to screen effective survivin siRNA sequences. The effect of vector-based survivin short hairpin RNA (shRNA) on the malignant phenotype of HCC cells in vitro and in vivo was determined, and an adenovirusmediated shRNA expression vector was developed to decrease survivin expression of the established HCC tumor in nude mice. In vitro study showed that stable survivin knockdown inhibited cancer cell proliferation, enhanced apoptotic susceptibility, arrested cell cycle in the G1 phase and resulted in apparent mitotic catastrophe. Moreover, cells stably expressing survivin shRNA showed decreased tumorigenicity in nude mice. An additional in vivo study showed that intratumoral injection of adenovirus-delivered survivin shRNA suppressed tumor growth by spontaneous apoptosis of cancer cells and significantly prolonged animal survival. In conclusion, we proved the therapeutic potential of survivin shRNA for the treatment of HCC. And our results indicated that adenovirus-delivered shRNA may serve as a novel therapeutic for HCC.

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“…33,34 As a result, activated PanP-DM1 only showed minimal dosedependent inhibitory activity in these cell lines (Fig 3C), which is equal to that of a control ADC, anti-tumor necrosis factor (TNF) mAb-DM1. Only activated PanP-DM1 at a high concentration (1 mg/ml) inhibited the growth of BT-474 or MCF-7 cells, indicating a non-specifically inhibitory effect.…”

Section: Panp-dm1 Has Superior In Vitro Anti-tumor Activity Compared mentioning

confidence: 93%

Preclinical studies of a Pro-antibody-drug conjugate designed to selectively target EGFR-overexpressing tumors with improved therapeutic efficacy

Yang¹,

Guo²,

Chen³

et al. 2016

mAbs

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Antibody-drug conjugates (ADCs) have exhibited potent clinical benefits in cancer therapy. However, development of ADCs against epidermal growth factor receptor (EGFR) has limitations because of wide expression of EGFR in both normal and tumor tissues. Previously, we developed an anti-EGFR proteaseactivated antibody (pro-antibody), termed as PanP, which remains inert against EGFR until activated by tumor-specific protease. Herein, we for the first time report a new class of pro-antibody-drug conjugate (PDC) against EGFR, denoted as PanP-DM1. It has been designed to selectively target the EGFRoverexpressing tumor cells and exert greater anti-tumor activity compared with PanP. Our data showed that PanP-DM1 also could be selectively activated by tumor-specific protease 'uPA'. Furthermore, activated PanP-DM1 was potently cytotoxic against EGFR-overexpressing tumor cell lines in vitro. Crucially, our data indicated that PanP-DM1 was significantly more effective in eradicating EGFR-overexpressing tumors in vivo. Additionally, toxicity was preliminarily evaluated in mice as measured by body weight loss. In summary, our study suggests that PanP-DM1, a novel pro-antibody-drug conjugate, has cancer-selectivity, efficacy and safety profile that supports its potential use for EGFR-overexpressing tumors.

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Survival of Cancer Cells Is Maintained by EGFR Independent of Its Kinase Activity

Cited by 434 publications

References 44 publications

Epidermal growth factor receptor expression escapes androgen regulation in prostate cancer: a potential molecular switch for tumour growth

Epidermal growth factor receptor expression escapes androgen regulation in prostate cancer: a potential molecular switch for tumour growth

Survivin knockdown by short hairpin RNA abrogates the growth of human hepatocellular carcinoma xenografts in nude mice

Preclinical studies of a Pro-antibody-drug conjugate designed to selectively target EGFR-overexpressing tumors with improved therapeutic efficacy

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