SMO Gene Amplification and Activation of the Hedgehog Pathway as Novel Mechanisms of Resistance to Anti-Epidermal Growth Factor Receptor Drugs in Human Lung Cancer

Corte, Carminia Maria Della; Bellevicine, Claudio; Vicidomini, Giovanni; Vitagliano, Donata; Malapelle, Umberto; Accardo, Marina; Fabozzi, Alessio; Fiorelli, Alfonso; Fasano, Morena; Papaccio, Federica; Martinelli, Erika; Troiani, Teresa; Troncone, Giancarlo; Santini, Mario; Bianco, Roberto; Ciardiello, Fortunato

doi:10.1158/1078-0432.ccr-14-3319

Cited by 100 publications

(107 citation statements)

References 32 publications

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“…Other receptors, such as AXL and ERBB2, did not show increased activity (Figure 5A). These results confirmed the role of Hh pathway as important mediator of resistance to first generation EGFR-TKIs [6] and revealed that Hh activation is maintained through several lines of therapies with EGFR inhibitors.…”

Section: Resultssupporting

confidence: 81%

“…To investigate if the activating Hh and MET signals are the consequence of gene amplification, as previously demonstrated [4, 6], we performed FISH analysis on resistant tumor samples, by the use of specific probes for MET and SMO genes. However, the mean gene copy number of both genes resulted similar in pretreated and resistant samples (data not shown).…”

Section: Resultsmentioning

confidence: 99%

“…Mechanisms of resistance to first-generation EGFR-TKIs are widely known and include for the majority of cases the onset of the second-site EGFR mutation substituting threonine for methionine at position 790 in exon 20 (T790M), the activation of other cellular signaling such as MET [4], ERBB2, AXL [5], Hedgehog (Hh) [6] or of downstream escape mediators (BRAF, PIK3CA) and histological changes as epithelial-to-mesenchymal transition (EMT) and small cell lung cancer (SCLC) [7, 8]. …”

Section: Introductionmentioning

confidence: 99%

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Efficacy of continuous EGFR-inhibition and role of Hedgehog in EGFR acquired resistance in human lung cancer cells with activating mutation of EGFR

et al. 2017

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PurposeThe aim of this work was to investigate the efficacy of sequential treatment with first-, second- and third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors and the mechanisms of acquired resistance occurring during the sequential use of these inhibitors.Experimental designWe developed an in vivo model of acquired resistance to EGFR-inhibitors by treating nude mice xenografted with HCC827, a human non-small-cell lung cancer (NSCLC) cell line harboring EGFR activating mutation, with a sequence of first-generation EGFR tyrosine kinase inhibitors (EGFR-TKIs) (erlotinib and gefitinib), of second-generation EGFR-TKI (afatinib) plus/minus the anti-EGFR monoclonal antibody cetuximab, and of third-generation EGFR-TKI (osimertinib).ResultsHCC827-derived xenografts and with acquired resistance to EGFR-inhibitors were sensitive to the sequential use of first-, second- and third-generation EGFR-TKIs. Continuous EGFR inhibition of first-generation resistant tumors by sequential treatment with afatinib plus/minus cetuximab, followed by osimertinib, represented an effective therapeutic strategy in this model. Whereas T790M resistance mutation was not detected, a major mechanism of acquired resistance was the activation of components of the Hedgehog (Hh) pathway. This phenomenon was accompanied by epithelial-to-mesenchymal transition. Cell lines established in vitro from gefitinib-, or afatinib- or osimertinib-resistant tumors showed metastatic properties and maintained EGFR-TKIs resistance in vitro, that was reverted by the combined blockade of Hh, with the selective SMO inhibitor sonidegib, and EGFR.ConclusionsEGFR-mutant NSCLC can benefit from continuous treatment with EGFR-inhibitors, indepenently from mechanisms of resistance. In a complex and heterogenous scenario, Hh showed an important role in mediating resistance to EGFR-inhibitors through the induction of mesenchymal properties.

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Section: Resultssupporting

confidence: 81%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Efficacy of continuous EGFR-inhibition and role of Hedgehog in EGFR acquired resistance in human lung cancer cells with activating mutation of EGFR

et al. 2017

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“…However, the other cell population harbored a BRAF mutation and was resistant to anti-EGFR therapies. In addition, in studies of non-small cell lung cancer cells, the activation of hedgehog activity (increased SMO, GLI1, and PTCH1 expression) was demonstrated to be important in the acquired resistance to a tyrosine kinase inhibitor, gefitinib [60]. GLI1 expression was also linked to acquired resistance to the anti-EGFR antibody cetuximab in squamous cell carcinoma, but was overcome by combined treatment with cetuximab and a hedgehog inhibitor [61].…”

Section: Epidermal Growth Factor Receptor (Egfr)mentioning

confidence: 99%

Molecular Signaling in Benign Odontogenic Neoplasia Pathogenesis

Amm

MacDougall

2016

Curr Oral Health Rep

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Several molecular pathways have been shown to play critical roles in the pathogenesis of odontogenic tumors. These neoplasms arise from the epithelial or mesenchymal cells of the dental apparatus in the jaw or oral mucosa. Next generation genomic sequencing has identified gene mutations or single nucleotide polymorphisms associated with many of these tumors. In this review, we focus on two of the most common odontogenic tumor subtypes: ameloblastoma and keratocystic odontogenic tumors. We highlight gene expression and protein immunohistological findings and known genetic alterations in the hedgehog, BRAF/Ras/MAPK, epidermal growth factor receptor, Wnt and Akt signaling pathways relevant to these tumors. These various pathways are explored to potentially target odontogenic tumors cells and prevent growth and recurrence of disease. Through an understanding of these signaling pathways and their crosstalk, molecular diagnostics may emerge as well as the ability to exploit identified molecular differences to develop novel molecular therapeutics for the treatment of odontogenic tumors.

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“…Moreover, LDE225 treatment attenuated the TKI-resistant NSCLC cell line HCC827-GR (gefitinib resistant) derived tumor growth. In addition, cotreatment of SMO inhibitor and MET inhibitor to HCC827-GR xenografted tumors further suppressed tumor volume, since constitutive MET activation was observed in HCC827-GR cells [97]. Moreover, RNAi-mediated GLI1 knockdown suppressed tumor formation and tumor sphere formation.…”

Section: Hh Signaling Pathway-targeted Cancer Therapy In Lung Cancermentioning

confidence: 99%

The Hedgehog Signaling Networks in Lung Cancer: The Mechanisms and Roles in Tumor Progression and Implications for Cancer Therapy

Abe

Tanaka

2016

BioMed Research International

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Lung cancer is the most common cause of cancer-related death worldwide and is classified into small cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC). Several gene mutations that contribute to aberrant cell proliferation have been identified in lung adenocarcinoma, a part of NSCLC. Various anticancer drugs that target these mutated molecules have been developed for NSCLC treatment. However, although molecularly targeted drugs are initially effective for patients, the 5-year survival rate remains low because of tumor relapse. Therefore, more effective drugs for lung cancer treatment should be developed. The hedgehog (HH) signaling pathway contributes to organ development and stem cell maintenance, and aberrant activation of this signaling pathway is observed in various cancers including lung cancer. In lung cancer, HH signaling pathway upregulates cancer cell proliferation and maintains cancer stem cells as well as cancer-associated fibroblasts (CAFs). Furthermore, physical contact between CAFs and NSCLC cells induces HH signaling pathway activation in NSCLC cells to enhance their metastatic potential. Therefore, HH signaling pathway inhibitors could be a useful option for lung cancer therapy.

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SMO Gene Amplification and Activation of the Hedgehog Pathway as Novel Mechanisms of Resistance to Anti-Epidermal Growth Factor Receptor Drugs in Human Lung Cancer

Cited by 100 publications

References 32 publications

Efficacy of continuous EGFR-inhibition and role of Hedgehog in EGFR acquired resistance in human lung cancer cells with activating mutation of EGFR

Efficacy of continuous EGFR-inhibition and role of Hedgehog in EGFR acquired resistance in human lung cancer cells with activating mutation of EGFR

Molecular Signaling in Benign Odontogenic Neoplasia Pathogenesis

The Hedgehog Signaling Networks in Lung Cancer: The Mechanisms and Roles in Tumor Progression and Implications for Cancer Therapy

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