Phosphorylated EGFR expression may predict outcome of EGFR-TKIs therapy for the advanced NSCLC patients with wild-type EGFR

Wang, Fen; Wang, Shuhang; Wang, Zhijie; Duan, Jianchun; An, Tongtong; Zhao, Jun; Bai, Hua; Wang, Jie

doi:10.1186/1756-9966-31-65

Cited by 40 publications

(41 citation statements)

References 39 publications

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“…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). These data suggest that site-specific phosphorylation of EGFR plays an important role in the maintenance of TKI resistance and that targeting these selective EGFR phosphorylations could be a future direction for drug discovery.…”

Section: Discussionmentioning

confidence: 86%

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.

101

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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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Section: Discussionmentioning

confidence: 86%

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.

101

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“…EGFR is a 170 kDa tyrosine kinase receptor consisting of an extracellular ligand-binding domain, a transmembrane lipophilic domain, and an intracellular tyrosine kinase domain and the C-terminus region with multiple tyrosine residues [26]. EGFR mediates signals that stimulate proliferation, migration, and metastasis in many tumour types [25,27], and its signal transduction is regulated by stimulatory and inhibitory inputs.…”

Section: Discussionmentioning

confidence: 99%

Restoration of LRIG1 suppresses bladder cancer cell growth by directly targeting EGFR activity

Chang

Shi

Yang

et al. 2013

J Exp Clin Cancer Res

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BackgroundRecently, leucine-rich repeats and immunoglobulin-like domains 1 (LRIG1), a negative regulator of EGFR, was discovered is a novel agent for suppressing bladder cancer. The aim of this study was to investigate the impact of LRIG1 on the biological features of aggressive bladder cancer cells and the possible mechanisms of enhanced apoptosis induced by upregulation of LRIG1.MethodsIn this study, we examined the mRNA and protein expression of LRIG1 and EGFR in bladder cancers and normal bladder. Meanwhile, we overexpressed LRIG1 with adenovirus vector in T24/5637 bladder cancer cell lines, and we used real time-PCR, western blot, and co-immunoprecipitation analysis in order to examine the effects of LRIG1 gene on EGFR. Furthermore, we evaluate the impact of LRIG1 gene on the function of human bladder cancer cells and EGFR signaling.ResultsThe expression of LRIG1 was decreased, while the expression of EGFR was increased in the majority of bladder cancer, and the ratio of EGFR/LRIG1 was increased in tumors versus normal tissue. We found that upregulation of LRIG1 induced cell apoptosis and cell growth inhibition, and further reversed invasion in bladder cancer cell lines in vitro by inhibiting phosphorylation of downstream MAPK and AKT signaling pathway.ConclusionTaken together, our findings provide us with an insight into LRIG1 function, and we conclude that LRIG1 evolved in bladder cancer as a rare feedback negative attenuator of EGFR, thus could offer a novel therapeutic target to treat patients with bladder cancer.

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“…Despite its effectiveness, a considerable fraction of patients do not respond to the treatment. EGFR pY1068 has emerged as a predictive biomarker for screening patients with wild-type EGFR that will respond to Gefitinib [128]. Imatinib (Gleevec) is another anti-cancer drug targeting the constitutively active BCR-Abl tyrosine kinase that results in chronic myeloid leukaemia (CML).…”

Section: Targeted Phosphoproteomics: Potential Clinical Applicationsmentioning

confidence: 99%

Targeted mass spectrometry: An emerging powerful approach to unblock the bottleneck in phosphoproteomics

Osinalde

Aloria

Omaetxebarria

et al. 2017

Journal of Chromatography B

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Phosphorylated EGFR expression may predict outcome of EGFR-TKIs therapy for the advanced NSCLC patients with wild-type EGFR

Cited by 40 publications

References 39 publications

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

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

Restoration of LRIG1 suppresses bladder cancer cell growth by directly targeting EGFR activity

Targeted mass spectrometry: An emerging powerful approach to unblock the bottleneck in phosphoproteomics

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