Cross-talk between EGFR and IL-6 drives oncogenic signaling and offers therapeutic opportunities in cancer

Ray, Kriti; Újvári, Beáta; Ramana, Venkata; Donald, John A.

doi:10.1016/j.cytogfr.2018.04.002

Cited by 37 publications

(20 citation statements)

References 109 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Such a cross-talk was found to be operative in an epithelial tumor model (42) and studies employing Drosophila found a robust interaction between both signaling systems (43). The interaction between EGFR and STAT signaling often employs cytokines of the JAK/STAT signaling pathway that are released upon EGFR pathway activation (44). A similar situation is found in our model, where we observed a massive upregulation of upd2 and upd3, which both code for ligands of the JAK/STAT signaling pathways.…”

Section: Discussionsupporting

confidence: 79%

“…A similar situation is found in our model, where we observed a massive upregulation of upd2 and upd3, which both code for ligands of the JAK/STAT signaling pathways. Synergistically targeting EGFR and JAK/STAT pathway for cancer therapy is intriguing in two ways: (i) because the IL6, or more generally the gp130 signaling pathway correlated with metastasis and epithelial-mesenchymal transition in lung cancer (45), this metastatic behavior might be dampened, and (ii) IL6-mediated signaling plays an important role in the development of treatment resistance, which can be specifically targeted by a combined approach (44,46,47). Thus, the combination of a TKI and a JAK/STAT inhibitor could be a promising and potential drug in treating lung cancer (48).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

An EGFR-InducedDrosophilaLung Tumor Model Identifies Alternative Combination Treatments

Bossen

Uliczka

Steen

et al. 2019

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

Lung cancer is the leading cause of cancer-associated mortality. Mutations in the EGFR gene are among the most important inducers of lung tumor development, but success of personalized therapies is still limited because of toxicity or developing resistances. We expressed constitutively active EGFR (EGFR CA) exclusively in the airway system of Drosophila melanogaster and performed comprehensive phenotyping. Ectopic expression of EGFR CA induced massive hyper-and metaplasia, leading to early death. We used the lethal phenotype as a readout and screened a library of FDA-approved compounds and found that among the 1,000 compounds, only the tyrosine kinase inhibitors (TKI) afatinib, gefitinib, and ibrutinib rescued lethality in a whole-animal screening approach. Furthermore, we screened the library in the presence of a subtherapeutic afatinib dose and identified bazedoxifene as a synergistically acting compound that rescues EGFRinduced lethality. Our findings highlight the potential of Drosophila-based whole-animal screening approaches not only to identify specific EGFR inhibitors but also to discover compounds that act synergistically with known TKIs. Moreover, we showed that targeting the EGFR together with STAT-signaling is a promising strategy for lung tumor treatment.

show abstract

Section: Discussionsupporting

confidence: 79%

Section: Discussionmentioning

confidence: 99%

An EGFR-InducedDrosophilaLung Tumor Model Identifies Alternative Combination Treatments

Bossen

Uliczka

Steen

et al. 2019

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

show abstract

“…Cancers 2019, 11,1927 6 of 18 dependent on the levels of Bcl-2 family proteins [23]. In this study, the expression levels of Bcl-2 family proteins in TMS-TMF-4f-treated cervical cancer cells were determined by Western blot analysis.…”

Section: Tms-tmf-4f Induces Mitochondria-dependent Apoptosis By Regulmentioning

confidence: 96%

“…Under normal conditions, STAT3 activation is tightly regulated by the presence or absence of polypeptide ligands bound to its receptor. However, in cancer cells, cytokine and growth factor receptors become constitutively activated, most commonly by the autocrine or paracrine expression of their respective ligands such as interleukin 6 (IL-6) and epidermal growth factor (EGF) [11]. The STAT3 signaling cascade is triggered by upstream kinase signals such as Janus kinase (JAK) and Src, resulting in the phosphorylation and activation of STAT3 monomers.…”

Section: Introductionmentioning

confidence: 99%

The Anti-Proliferative Activity of the Hybrid TMS-TMF-4f Compound Against Human Cervical Cancer Involves Apoptosis Mediated by STAT3 Inactivation

Hong

Chung

Shin

et al. 2019

Cancers

View full text Add to dashboard Cite

We previously reported the potential anti-proliferative activity of 3-(5,6,7-trimethoxy-4-oxo-4H-chromen-2-yl)-N-(3,4,5-trimethoxyphenyl) benzamide (TMS-TMF-4f) against human cancer cells; however, the underlying molecular mechanisms have not been investigated. In the present study, TMS-TMF-4f showed the highest cytotoxicity in human cervical cancer cells (HeLa and CaSki) and low cytotoxicity in normal ovarian epithelial cells. Annexin V-FITC and propidium iodide (PI) double staining revealed that TMS-TMF-4f-induced cytotoxicity was caused by the induction of apoptosis in both HeLa and CaSki cervical cancer cells. The compound TMS-TMF-4f enhanced the activation of caspase-3, caspase-8, and caspase-9 and regulated Bcl-2 family proteins, which led to mitochondrial membrane potential (MMP) loss and resulted in the release of cytochrome c and Smac/DIABLO into the cytosol. Also, TMS-TMF-4f suppressed both constitutive and IL-6-inducible levels of phosphorylated STAT3 (p-STAT3) and associated proteins such as Mcl-1, cyclin D1, survivin, and c-Myc in both cervical cancer cells. STAT-3 overexpression completely ameliorated TMS-TMF-4f-induced apoptotic cell death and PARP cleavage. Docking analysis revealed that TMS-TMF-4f could bind to unphosphorylated STAT3 and inhibit its interconversion to the activated form. Notably, intraperitoneal administration of TMS-TMF-4f (5, 10, or 20 mg/kg) decreased tumor growth in a xenograft cervical cancer mouse model, demonstrated by the increase in TUNEL staining and PARP cleavage and the reduction in p-STAT3, Mcl-1, cyclin D1, survivin, and c-Myc expression levels in tumor tissues. Taken together, our results suggest that TMS-TMF-4f may potentially inhibit human cervical tumor growth through the induction of apoptosis via STAT3 suppression.

show abstract

“…It has been reported that elevated IL-6 levels autocrined by cancer cells because of a mutation in the EGFR kinase domain or that existing in the tumor microenvironment leads to overexpression of signal transducer and activator of transcription 3 through activation of the gp130/Janus kinase 1 pathway or IL-6R/Janus kinase 1/ signal transducer and activator of transcription 3 pathway, which may further promote secondary resistance to EGFR tyrosine kinase inhibitors in patients with NSCLC with mutant EGFR. 3,4 Therefore, we speculate that the differences in IL-6 levels may further affect the process of drug resistance by regulating the tumor microenvironment and that patients with elevated IL-6 levels may be more prone to earlier development of secondary drug resistance, thus widening the survival gap between those with high and low IL-6 levels. In addition, we would like to conjecture that IL-6 inhibitors in combination with EGFR tyrosine kinase inhibitors may enhance the efficacy of targeted therapy.…”

mentioning

confidence: 99%

Association between Circulating Inflammatory Proteins and Clinical Prognosis in Chinese Patients with EGFR Mutation–Positive Non–Small Cell Lung Cancer

Guan

Lin

Luo

et al. 2019

Journal of Thoracic Oncology

View full text Add to dashboard Cite

We read with interest the article titled "Circulating Inflammation Proteins Associated with Lung Cancer in African Americans" by Claire et al., in which they revealed that elevated interleukin-6 (IL-6) and C-reactive protein (CRP) levels were associated with a poor prognosis in patients with lung cancer. 1 Given that differences in tumor biology might affect the universality of results across populations, we collected relevant data from the Zhujiang Hospital of Southern Medical University (Table 1), referring to the inclusion and exclusion criteria of this article, 1 to explore the effects of IL-6 and CRP levels on the prognosis of patients with lung cancer in the People's Republic of China. Studies have shown that the prevalence of EGFR mutations in patients with NSCLC is approximately 19% in Western countries, whereas the corresponding incidence in Asia is approximately 48%. 2 Considering such differences among populations, a subgroup analysis was designed on the basis EGFR testing results (mutant versus wild-type) determined by using the amplification refractory mutation system method. Of the 372 patients enrolled, 68 patients with NSCLC underwent EGFR mutation testing, and the results showed 38 with an EGFR mutation and 30 with wild-type EGFR. According to the medians of the inflammatory proteins (IL-6 and CRP), we divided the 372 patients into corresponding high-value and low-value groups. A survival analysis based on IL-6, CRP, and a combined CRP and IL-6 classifier showed that for all patients, elevated inflammatory protein levels predicted a poor prognosis (Fig. 1A-C), which was consistent with the results of Claire et al. In the subgroup analysis, we observed an interesting phenomenon: in patients with EGFR-mutated NSCLC, the results were in accordance with the overall results (Fig. 1D-F), whereas in patients with EGFR wild-Drs. Guan and Luo contributed equally to this work.

show abstract

Cross-talk between EGFR and IL-6 drives oncogenic signaling and offers therapeutic opportunities in cancer

Cited by 37 publications

References 109 publications

An EGFR-InducedDrosophilaLung Tumor Model Identifies Alternative Combination Treatments

An EGFR-InducedDrosophilaLung Tumor Model Identifies Alternative Combination Treatments

The Anti-Proliferative Activity of the Hybrid TMS-TMF-4f Compound Against Human Cervical Cancer Involves Apoptosis Mediated by STAT3 Inactivation

Association between Circulating Inflammatory Proteins and Clinical Prognosis in Chinese Patients with EGFR Mutation–Positive Non–Small Cell Lung Cancer

Contact Info

Product

Resources

About