Dataset Information

HER3 expression and MEK activation in non-small-cell lung carcinoma.

ABSTRACT:

Aim

We explore HER3 expression in lung adenocarcinoma (adeno-NSCLC) and identify potential mechanisms of HER3 expression.

Materials & methods

Tumor samples from 45 patients with adeno-NSCLC were analyzed. HER3 and HER2 expression were identified using immunohistochemistry and bioinformatic interrogation of The Cancer Genome Atlas (TCGA).

Results

HER3 was highly expressed in 42.2% of cases. ERBB3 copy number did not account for HER3 overexpression. Bioinformatic analysis of TCGA demonstrated that MEK activity score (a surrogate of functional signaling) did not correlate with HER3 ligands. ERBB3 RNA expression levels were significantly correlated with MEK activity after adjusting for EGFR expression.

Conclusion

HER3 expression is common and is a potential therapeutic target by virtue of frequent overexpression and functional downstream signaling.

SUBMITTER: Manickavasagar T

PROVIDER: S-EPMC8162178 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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Publications

HER3 expression and MEK activation in non-small-cell lung carcinoma.

Manickavasagar Thubeena T Yuan Wei W Carreira Suzanne S Gurel Bora B Miranda Susana S Ferreira Ana A Crespo Mateus M Riisnaes Ruth R Baker Chloe C O'Brien Mary M Bhosle Jaishree J Popat Sanjay S Banerji Udai U Lopez Juanita J de Bono Johann J Minchom Anna A

Lung cancer management 20210409 2

<h4>Aim</h4>We explore HER3 expression in lung adenocarcinoma (adeno-NSCLC) and identify potential mechanisms of HER3 expression.<h4>Materials & methods</h4>Tumor samples from 45 patients with adeno-NSCLC were analyzed. HER3 and HER2 expression were identified using immunohistochemistry and bioinformatic interrogation of The Cancer Genome Atlas (TCGA).<h4>Results</h4>HER3 was highly expressed in 42.2% of cases. <i>ERBB3</i> copy number did not account for HER3 overexpression. Bioinformatic analy ...[more]

PMID: 34084213

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Project description:BackgroundAKT1 must be present and activated in the nucleus immediately after irradiation to stimulate AKT1-dependent double-strand breaks (DSB) repair through the fast non-homologous end-joining (NHEJ) repair process. We investigated the subcellular distribution of AKT1 and the role of HER family receptor members on the phosphorylation of nuclear AKT and radiation response.Materials and methodsUsing genetic approaches and pharmacological inhibitors, we investigated the subcellular distribution of AKT1 and the role of HER family receptor members on the activation of nuclear AKT in non-small cell lung cancer (NSCLC) cells in vitro. ɤH2AX foci assay was applied to investigate the role of AKT activating signaling pathway on DSB repair. A mouse tumor xenograft model was used to study the impact of discovered signaling pathway activating nuclear AKT on the radiation response of tumors in vivo.ResultsOur data suggests that neither ionizing radiation (IR) nor stimulation with HER family receptor ligands induced rapid nuclear translocation of endogenous AKT1. GFP-tagged exogenous AKT1 translocated to the nucleus under un-irradiated conditions and IR did not stimulate this translocation. Nuclear translocation of GFP-AKT1 was impaired by the AKT inhibitor MK2206 as shown by its accumulation in the cytoplasmic fraction. IR-induced phosphorylation of nuclear AKT was primarily dependent on HER3 expression and tyrosine kinase activation of epidermal growth factor receptor. In line with the role of AKT1 in DSB repair, the HER3 neutralizing antibody patritumab as well as HER3-siRNA diminished DSB repair in vitro. Combination of patritumab with radiotherapy improved the effect of radiotherapy on tumor growth delay in a xenograft model.ConclusionIR-induced activation of nuclear AKT occurs inside the nucleus that is mainly dependent on HER3 expression in NSCLC. These findings suggest that targeting HER3 in combination with radiotherapy may provide a logical treatment option for investigation in selected NSCLC patients.

Dataset Information

HER3 expression and MEK activation in non-small-cell lung carcinoma.

Aim

Materials & methods

Results

Conclusion

Publications

HER3 expression and MEK activation in non-small-cell lung carcinoma.

Similar Datasets

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