Genetic and pharmacologic inhibition of EPHA2 promotes apoptosis in NSCLC

Amato, Katherine; Wang, Shan; Hastings, Andrew K.; Youngblood, Victoria; Santapuram, Pranav R.; Chen, Haiying; Cates, Justin M.; Colvin, Daniel C.; Ye, Fei; Brantley-Sieders, Dana M.; Cook, Rebecca S.; Li, Tan; Gray, Nathanael S.; Jin, Chen

doi:10.1172/jci72522

Cited by 106 publications

(120 citation statements)

References 30 publications

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“…In the background of these observations, our studies show that lung tumor-specific knockdown of EphA2 exacerbates adenocarcinoma development similar to knockdown of Tp53. In contrast to EphA2 whole body knockout combined with KRas G12Dla2 transgenic mice studies (37), our experiments caused loss of EphA2 specifically in tumor cells and this deletion promoted tumor development in the context of tumor cell-specific expression of oncogenic KRas G12D . These observations suggest that EphA2 has different tumor cell autonomous and nonautonomous roles in tumor development.…”

Section: Discussioncontrasting

confidence: 61%

Screening for tumor suppressors: Loss of ephrin receptor A2 cooperates with oncogenic KRas in promoting lung adenocarcinoma

Narayana

Xia

et al. 2015

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

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Lung adenocarcinoma, a major form of non-small cell lung cancer, is the leading cause of cancer deaths. The Cancer Genome Atlas analysis of lung adenocarcinoma has identified a large number of previously unknown copy number alterations and mutations, requiring experimental validation before use in therapeutics. Here, we describe an shRNA-mediated high-throughput approach to test a set of genes for their ability to function as tumor suppressors in the background of mutant KRas and WT Tp53. We identified several candidate genes from tumors originated from lentiviral delivery of shRNAs along with Cre recombinase into lungs of Loxp-stop-Loxp-KRas mice. Ephrin receptorA2 (EphA2) is among the top candidate genes and was reconfirmed by two distinct shRNAs. By generating knockdown, inducible knockdown and knockout cell lines for loss of EphA2, we showed that negating its expression activates a transcriptional program for cell proliferation. Loss of EPHA2 releases feedback inhibition of KRAS, resulting in activation of ERK1/2 MAP kinase signaling, leading to enhanced cell proliferation. Intriguingly, loss of EPHA2 induces activation of GLI1 transcription factor and hedgehog signaling that further contributes to cell proliferation. Small molecules targeting MEK1/2 and Smoothened hamper proliferation in EphA2-deficient cells. Additionally, in EphA2 WT cells, activation of EPHA2 by its ligand, EFNA1, affects KRAS–RAF interaction, leading to inhibition of the RAS-RAF-MEK-ERK pathway and cell proliferation. Together, our studies have identified that (i) EphA2 acts as a KRas cooperative tumor suppressor by in vivo screen and (ii) reactivation of the EphA2 signal may serve as a potential therapeutic for KRas-induced human lung cancers.

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Section: Discussioncontrasting

confidence: 61%

Screening for tumor suppressors: Loss of ephrin receptor A2 cooperates with oncogenic KRas in promoting lung adenocarcinoma

Narayana

Xia

et al. 2015

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

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“…This compound inhibited EphA2 Tyr-588, as well as Akt, RSK, S6K1, S6, and BAD phosphorylation, to inhibit cancer viability in vitro in NSCLC cell lines, and inhibited NSCLC tumor growth by promoting tumor cell apoptosis and suppressing cell proliferation in vivo. 66) In the EGFR TKIresistant cells, ALW-II-41-27 suppressed cell viability and proliferation and promoted apoptosis. In addition, it decreased the tumor growth of resistant cells in vivo.…”

Section: Cell Survival and Proliferationmentioning

confidence: 99%

Emerging and Diverse Functions of the EphA2 Noncanonical Pathway in Cancer Progression

Zhou

Sakurai

2017

Biological & Pharmaceutical Bulletin

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Erythropoietin-producing hepatocellular receptor A2 (EphA2) receptor tyrosine kinase controls multiple physiological processes to maintain homeostasis in normal cells. In many types of solid tumors, it has been reported that EphA2 is overexpressed and plays a critical role in oncogenic signaling. However, in recent years, the opposing functions of EphA2 have been explained by the canonical and noncanonical signaling pathways. Ligand-and tyrosine kinase-dependent EphA2 activation (the canonical pathway) inhibits cancer cell proliferation and motility. In contrast, ligand-and tyrosine kinase-independent EphA2 signaling (the noncanonical pathway) promotes tumor survival and metastasis and controls acquired drug resistance and maintenance of cancer stem cell-like properties. Evidence has accumulated showing that the EphA2 noncanonical pathway is mainly regulated by inflammatory cytokines and growth factors via phosphorylation at Ser-897 in the intracellular C-tail region via some serine/threonine kinases, including p90 ribosomal S6 kinase. In this review, we focus on the regulation of Ser-897 phosphorylation and its functional importance in tumor malignancy and discuss future therapeutic targeting.

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“…Despite dichotomous roles of Eph receptors in cancer, kinase activity of the EphA2 receptor has been consistently linked to tumor promotion in breast cancer and in lung cancer (33, 55–57). Screening efforts to identify ATP-competitive, small molecule inhibitors of Eph RTKs have yielded inhibitors with nanomolar binding affinities to respective Eph RTKs (58).…”

Section: Kinase Inhibitorsmentioning

confidence: 99%

“…One of the compounds discovered to inhibit EphA2 activity, ALW-II-41-27, displayed potent activity in inducing apoptosis in non-small cell lung cancer cells and inhibited tumor growth in a xenograft model in vivo (57). Several lines of evidence suggest that ALW-II-41-27 can serve as a relatively selective EphA2 RTK inhibitor.…”

Section: Kinase Inhibitorsmentioning

confidence: 99%

Eph receptor tyrosine kinases in cancer stem cells

Chen

Song

Amato³

2015

Cytokine & Growth Factor Reviews

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Eph receptor tyrosine kinases (RTKs) and their ligands, ephrins, play critical roles in development, tissue homeostasis, and cancer. Because Eph receptors are expressed in most adult stem cell niches and in many types of cancers, it has been long suspected that this family of RTKs may also regulate the function of cancer stem-like cells (CSCs). This review will focus on recent studies to elucidate the contribution of Eph/ephrin molecules in CSC self-renewal and tumorigenicity, as well as describe efforts to target these molecules in cancer. Because CSCs are often resistant to therapeutic intervention and have been shown to depend on Eph RTKs for self-renewal, targeting Eph receptors may hold promise for the treatment of drug-resistant cancers.

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Genetic and pharmacologic inhibition of EPHA2 promotes apoptosis in NSCLC

Abstract: Genome-wide analyses determined previously that the receptor tyrosine kinase (RTK) EPHA2 is commonly

Cited by 106 publications

References 30 publications

Screening for tumor suppressors: Loss of ephrin receptor A2 cooperates with oncogenic KRas in promoting lung adenocarcinoma

Screening for tumor suppressors: Loss of ephrin receptor A2 cooperates with oncogenic KRas in promoting lung adenocarcinoma

Emerging and Diverse Functions of the EphA2 Noncanonical Pathway in Cancer Progression

Eph receptor tyrosine kinases in cancer stem cells

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