Access to the Nucleus and Functional Association with c-Myc Is Required for the Full Oncogenic Potential of ΔEGFR/EGFRvIII

Gururaj, Anupama E.; Gibson, Laura A.; Panchabhai, Sonali; Bai, Ming Hui; Manyam, Ganiraju C.; Lu, Yue; Latha, Khatri; Rojas, Marta; Hwang, Yeohyeon; Liang, Shoudan; Bögler, Oliver

doi:10.1074/jbc.m112.399352

Cited by 15 publications

(14 citation statements)

References 38 publications

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“…Additionally, inhibition of SFK activity led to decreased phosphorylation of EGFR on Y1101 and reduced nEGFR levels (Figure 3C and 5A, 5B). Interestingly, Figure 5C indicates that surface level EGFR was enhanced within 24 hours of dasatinib treatment, even though a decrease in nEGFR expression was more prominent at later time points post treatment (Figure 5A and 5B); this suggests that the rate of nEGFR export, via its nuclear export sequence (28), varies between cell lines. Collectively, these data suggest that SFK phosphorylation of EGFR on Y1101 may be a critical step for EGFR nuclear translocation in TNBC.…”

Section: Discussionmentioning

confidence: 98%

“…Within the nucleus, EGFR can function as a co-transcription factor to regulate genes involved in tumor progression (10, 11), in addition to functioning as a nuclear kinase to enhance DNA replication and repair, (12–14). These nuclear functions have been linked to three parameters of tumor biology: 1) inverse correlation with overall survival in numerous cancers (15–20), 2) resistance to therapeutic agents including radiation (12, 21–24), chemotherapy (12, 13, 24), and anti-EGFR therapies gefitinib (25) and cetuximab (26), and 3) enhanced tumor growth (27, 28). These findings suggest that tumors rely on two distinct compartments of EGFR signaling to sustain their oncogenic phenotype: 1) classical membrane-bound EGFR signaling, and 2) nEGFR signaling.…”

Section: Introductionmentioning

confidence: 99%

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Nuclear Epidermal Growth Factor Receptor Is a Functional Molecular Target in Triple-Negative Breast Cancer

Brand

Iida²,

Dunn³

et al. 2014

Molecular Cancer Therapeutics

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Triple-negative breast cancer (TNBC) is a subclass of breast cancers (i.e. estrogen receptor negative, progesterone receptor negative, and HER2 negative) that have poor prognosis and very few identified molecular targets. Strikingly, a high percentage of TNBC’s overexpress the epidermal growth factor receptor (EGFR), yet EGFR inhibition has yielded little clinical benefit. Over the last decade, advances in EGFR biology have established that EGFR functions in two distinct signaling pathways: 1) classical membrane-bound signaling, and 2) nuclear signaling. Previous studies have demonstrated that nuclear EGFR (nEGFR) can enhance resistance to anti-EGFR therapies and is correlated with poor overall survival in breast cancer. Based on these findings we hypothesized that nEGFR may promote intrinsic resistance to cetuximab in TNBC. To examine this question, a battery of TNBC cell lines and human tumors were screened and found to express nEGFR. Knockdown of EGFR expression demonstrated that TNBC cell lines retained dependency on EGFR for proliferation, yet all cell lines were resistant to cetuximab. Further, Src Family Kinases (SFKs) influenced nEGFR translocation in TNBC cell lines and in vivo tumor models, where inhibition of SFK activity led to potent reductions in nEGFR expression. Inhibition of nEGFR translocation led to a subsequent accumulation of EGFR on the plasma membrane, which greatly enhanced sensitivity of TNBC cells to cetuximab. Collectively, these data suggest that targeting both the nEGFR signaling pathway, through the inhibition of its nuclear transport, and the classical EGFR signaling pathway with cetuximab may be a viable approach for the treatment of TNBC patients.

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Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Nuclear Epidermal Growth Factor Receptor Is a Functional Molecular Target in Triple-Negative Breast Cancer

Brand

Iida²,

Dunn³

et al. 2014

Molecular Cancer Therapeutics

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“…They stain positively for the GBM marker vimentin [66] and harbor activating mutations of the K-ras oncogene as well as mutations of the p53 tumor suppressor gene, resulting in high expression of c-myc [65]. Similar genetic derangements have been reported in human gliomas [67-69]. GL261 tumors are partially immunogenic, as they express high levels of MHC I.…”

Section: Gl261; C57bl/6 Modelmentioning

confidence: 95%

Immunocompetent murine models for the study of glioblastoma immunotherapy

et al. 2014

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Glioblastoma remains a lethal diagnosis with a 5-year survival rate of less than 10%. (NEJM 352:987-96, 2005) Although immunotherapy-based approaches are capable of inducing detectable immune responses against tumor-specific antigens, improvements in clinical outcomes are modest, in no small part due to tumor-induced immunosuppressive mechanisms that promote immune escape and immuno-resistance. Immunotherapeutic strategies aimed at bolstering the immune response while neutralizing immunosuppression will play a critical role in improving treatment outcomes for glioblastoma patients. In vivo murine models of glioma provide an invaluable resource to achieving that end, and their use is an essential part of the preclinical workup for novel therapeutics that need to be tested in animal models prior to testing experimental therapies in patients. In this article, we review five contemporary immunocompetent mouse models, GL261 (C57BL/6), GL26 (C57BL/6) CT-2A (C57BL/6), SMA-560 (VM/Dk), and 4C8 (B6D2F1), each of which offer a suitable platform for testing novel immunotherapeutic approaches.

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“…Journal of Oncology receptor activities. One of the most interesting analyses is focused on the nuclear role of EGFR vIII , as this function is suggested to be very relevant [144,145]. erefore, EGFR vIII interaction with oncostatin M receptor (OSMR) can be considered interesting, as it may be possible to design molecules inhibiting such interaction for therapeutic purposes [146].…”

Section: Egfr VIII Mechanism Of Actionmentioning

confidence: 99%

EGFR^vIII: An Oncogene with Ambiguous Role

Rutkowska

Stoczyńska-Fidelus

Janik

et al. 2019

Journal of Oncology

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Epidermal growth factor receptor variant III (EGFRvIII) seems to constitute the perfect therapeutic target for glioblastoma (GB), as it is specifically present on up to 28–30% of GB cells. In case of other tumor types, expression and possible role of this oncogene still remain controversial. In spite of EGFRvIII mechanism of action being crucial for the design of small active anticancer molecules and immunotherapies, i.e., CAR-T technology, it is yet to be precisely defined. EGFRvIII is known to be resistant to degradation, but it is still unclear whether it heterodimerizes with EGF-activated wild-type EGFR (EGFRWT) or homodimerizes (including covalent homodimerization). Constitutive kinase activity of this mutated receptor is relatively low, and some researchers even claim that a nuclear, but not a membrane function, is crucial for its activity. Based on the analyses of recurrent tumors that are often lacking EGFRvIII expression despite its initial presence in corresponding primary foci, this oncogene is suggested to play a marginal role during later stages of carcinogenesis, while even in primary tumors EGFRvIII expression is detected only in a small percentage of tumor cells, undermining the rationality of EGFRvIII-targeting therapies. On the other hand, EGFRvIII-positive cells are resistant to apoptosis, more invasive, and characterized with enhanced proliferation rate. Moreover, expression of this oncogenic receptor was also postulated to be a marker of cancer stem cells. Opinions regarding the role that EGFRvIII plays in tumorigenesis and for tumor aggressiveness are clearly contradictory and, therefore, it is crucial not only to determine its mechanism of action, but also to unambiguously define its role at early and advanced cancer stages.

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Access to the Nucleus and Functional Association with c-Myc Is Required for the Full Oncogenic Potential of ΔEGFR/EGFRvIII

Cited by 15 publications

References 38 publications

Nuclear Epidermal Growth Factor Receptor Is a Functional Molecular Target in Triple-Negative Breast Cancer

Nuclear Epidermal Growth Factor Receptor Is a Functional Molecular Target in Triple-Negative Breast Cancer

Immunocompetent murine models for the study of glioblastoma immunotherapy

EGFR^vIII: An Oncogene with Ambiguous Role

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Access to the Nucleus and Functional Association with c-Myc Is Required for the Full Oncogenic Potential of ΔEGFR/EGFRvIII

Cited by 15 publications

References 38 publications

Nuclear Epidermal Growth Factor Receptor Is a Functional Molecular Target in Triple-Negative Breast Cancer

Nuclear Epidermal Growth Factor Receptor Is a Functional Molecular Target in Triple-Negative Breast Cancer

Immunocompetent murine models for the study of glioblastoma immunotherapy

EGFRvIII: An Oncogene with Ambiguous Role

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EGFR^vIII: An Oncogene with Ambiguous Role