Epidermal growth factor receptor mutations in non-small cell lung cancer influence downstream Akt, MAPK and Stat3 signaling

Zimmer, Sebastian; Kahl, Philip; Buhl, Theresa; Steiner, Susanne; Wardelmann, Eva; Merkelbach‐Bruse, Sabine; Buettner, Reinhard; Heukamp, Lukas C.

doi:10.1007/s00432-008-0509-9

Cited by 47 publications

(38 citation statements)

References 28 publications

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“…There was no significant difference in pSTAT3 expression between the EGFR-mutated (83%) and EGFR-wild-type tumors (56%), and the expression of pSTAT3 was not a result of EGFR kinase activity in NSCLC [25]. pSTAT3 was generally observed irrespective of the EGFR mutation status in the present study, confirming previously published data [25].…”

Section: Discussionsupporting

confidence: 93%

“…pSTAT3 was generally observed irrespective of the EGFR mutation status in the present study, confirming previously published data [25]. Although their analysis included squamous cell carcinoma at a more advanced stage, the researchers suggested that STAT3 activity contributes to the carcinogenic potential of NSCLC independent of EGFR mutations.…”

Section: Discussionsupporting

confidence: 92%

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STAT3 expression in activating EGFR-driven adenocarcinoma of the lung

et al. 2012

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 92%

STAT3 expression in activating EGFR-driven adenocarcinoma of the lung

et al. 2012

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“…For example, the phosphorylation of Y1068 can recruit GAB-1 or growth factor receptor-bound protein 2 (Grb-2) to activate survival signals (40), whereas the phosphorylation of Y1173 is responsible for eliciting the activation of ERK via inhibition of the SH2 domain-containing transforming protein (SHC) and Grb2 (41,42). Furthermore, the up-regulation of pY1173 also has been reported in patients who have NSCLC with EGFR mutation, and Akt, MAPK, and Stat3 signaling is higher in pY1173-positive patients (43). It also has been shown that patients with stage IIIb and IV NSCLC with positive pY1173 staining have a shorter superior progression-free survival rate than patients with negative pY1173 staining (44).…”

Section: Discussionmentioning

confidence: 99%

Effect of sialylation on EGFR phosphorylation and resistance to tyrosine kinase inhibition

Yen

Liu²,

Chen³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Epidermal growth factor receptor (EGFR) is a heavily glycosylated transmembrane receptor tyrosine kinase. Upon EGF-binding, EGFR undergoes conformational changes to dimerize, resulting in kinase activation and autophosphorylation and downstream signaling. Tyrosine kinase inhibitors (TKIs) have been used to treat lung cancer by inhibiting EGFR phosphorylation. Previously, we demonstrated that EGFR sialylation suppresses its dimerization and phosphorylation. In this report, we further investigated the effect of sialylation on the phosphorylation profile of EGFR in TKIsensitive and TKI-resistant cells. Sialylation was induced in cancer progression to inhibit the association of EGFR with EGF and the subsequent autophosphorylation. In the absence of EGF the TKIresistant EGFR mutant (L858R/T790M) had a higher degree of sialylation and phosphorylation at Y1068, Y1086, and Y1173 than the TKI-sensitive EGFR. In addition, although sialylation in the TKIresistant mutants suppresses EGFR tyrosine phosphorylation, with the most significant effect on the Y1173 site, the sialylation effect is not strong enough to stop cancer progression by inhibiting the phosphorylation of these three sites. These findings were supported further by the observation that the L858R/T790M EGFR mutant, when treated with sialidase or sialyltransferase inhibitor, showed an increase in tyrosine phosphorylation, and the sensitivity of the corresponding resistant lung cancer cells to gefitinib was reduced by desialylation and was enhanced by sialylation.E pidermal growth factor receptor (EGFR), one of the most studied receptor tyrosine kinases, is a drug target for cancer therapy, because its kinase activity correlates with tumorigenicity (1). Under normal conditions, EGFR forms dimers upon ligand binding and induces kinase activation (2-6). The conformational change of EGFR from tethered to extended form induced by ligand binding involves the exposure of the interface, followed by dimerization, activation, and autophosphorylation (7). The phosphorylation code of EGFR determines the propensity of the downstream signaling network to regulate cell proliferation, survival, migration, and angiogenesis (8, 9).In a significant fraction of patients with nonsmall cell lung cancer (NSCLC), especially patients in Asia and those with the adenocarcinoma subtype, mutations in the kinase domain of EGFR cause constitutive activation and have been identified as an important factor in EGFR dysregulation (10, 11). Particularly, mutation from leucine to arginine at position 858 (L858R) and, less significantly, deletion of exon 19 that eliminates four amino acids (LREA) account for ∼90% of the mutations involved in the constitutive activation of EGFR. These mutations are commonly found in patients with increased sensitivity to EGFR tyrosine kinase inhibitors (TKIs) such as gefitinib and erlotinib (12-14). However, most patients with such mutations show resistance within months after TKI therapy, and >50% of them develop a second EGFR mutation, T790M, which confers TKI resi...

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“…STAT3 may be one of the key oncogenic drivers in NSCLC. [6][7][8][9][10][11][12][13][14] However, several studies have found that STAT3 also plays a role in tumor suppression, [15][16][17][18][19] which should be taken into consideration in cancer therapies based on STAT3 inhibition. In this review, we focus on the molecular function of STAT3.…”

Section: Introductionmentioning

confidence: 99%

Role of STAT3 in lung cancer

Dutta

Sabri

et al. 2014

JAK-STAT

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Lung cancer remains a challenging disease. It is responsible for the high cancer mortality rates in the US and worldwide. Elucidation of the molecular mechanisms operative in lung cancer is an important first step in developing effective therapies. Accumulating evidence over the last 2 decades suggests a critical role for Signal Transducer and Activator of Transcription 3 (STAT3) as a point of convergence for various signaling pathways that are dysregulated in the disease. In this review, we discuss possible molecular mechanisms involving STAT3 in lung tumorigenesis based on recent literature. We consider possible roles of STAT3 in cancer cell proliferation and survival, in the tumor immune environment, and in epigenetic regulation and interaction of STAT3 with other transcription factors. We also discuss the potential role of STAT3 in tumor suppression, which complicates strategies of targeting STAT3 in cancer therapy.

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Epidermal growth factor receptor mutations in non-small cell lung cancer influence downstream Akt, MAPK and Stat3 signaling

Cited by 47 publications

References 28 publications

STAT3 expression in activating EGFR-driven adenocarcinoma of the lung

STAT3 expression in activating EGFR-driven adenocarcinoma of the lung

Effect of sialylation on EGFR phosphorylation and resistance to tyrosine kinase inhibition

Role of STAT3 in lung cancer

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