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
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Abstract
PURPOSE: Resistance to tyrosine kinase inhibitors (TKI) of EGF receptor (EGFR) is often related to activation of other signaling pathways and evolution through a mesenchymal phenotype. EXPERIMENTAL DESIGN: Because the Hedgehog (Hh) pathway has emerged as an important mediator of epithelial-to-mesenchymal transition (EMT), we studied the activation of Hh signaling in models of EGFR-TKIs intrinsic or acquired resistance from both EGFR-mutated and wild-type (WT) non-small cell lung cancer (NSCLC) cell lines. RESULTS: Activation of the Hh pathway was found in both models of EGFR-mutated and EGFR-WT NSCLC cell line resistant to EGFR-TKIs. In EGFR-mutated HCC827-GR cells, we found SMO (the Hh receptor) gene amplification, MET activation, and the functional interaction of these two signaling pathways. In HCC827-GR cells, inhibition of SMO or downregulation of GLI1 (the most important Hh-induced transcription factor) expression in combination with MET inhibition exerted significant antitumor activity.In EGFR-WT NSCLC cell lines resistant to EGFR inhibitors, the combined inhibition of SMO and EGFR exerted a strong antiproliferative activity with a complete inhibition of PI3K/Akt and MAPK phosphorylation. In addition, the inhibition of SMO by the use of LDE225 sensitizes EGFR-WT NSCLC cells to standard chemotherapy. CONCLUSIONS: This result supports the role of the Hh pathway in mediating resistance to anti-EGFR-TKIs through the induction of EMT and suggests new opportunities to design new treatment strategies in lung cancer.
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Another pathway recently identified in the EMT setting and responsible for acquisition of resistance to first-generation EGFR-TKIs is the Hedgehog (Hh) pathway.
“Another pathway recently identified in the EMT setting and responsible for acquisition of resistance to first-generation EGFR-TKIs is the Hedgehog (Hh) pathway,41”
From Mechanisms of resistance to EGFR-targeted drugs: lung cancer (2016) · cites this paper as [41]
The combined inhibition of both SMO and MET exerted a significant antiproliferative and proapoptotic effect concomitantly with the loss of mesenchymal features in preclinical models of acquired resistance to EGFR-TKIs in EGFR-mutated NSCLC cells.
“In this respect, the combined inhibition of both SMO and MET exerted a significant antiproliferative and proapoptotic effect concomitantly with the loss of mesenchymal features in preclinical models of acquired resistance to EGFR-TKIs in EGFR-mutated NSCLC cells, suggesting new combination strategies at the occurrence of resistance.”
From Mechanisms of resistance to EGFR-targeted drugs: lung cancer (2016) · cites this paper as [41]
Gene amplification of the Hh receptor, SMO, concomitantly with MET activation, has been recently identified, for the first time, as a novel mechanism of acquired resistance to EGFR-TKI in EGFR-mutant NSCLC cells.
“More deeply, gene amplification of the Hh receptor, SMO, concomitantly with MET activation, has been recently identified, for the first time, as a novel mechanism of acquired resistance to EGFR-TKI in EGFR-mutant NSCLC cells.”
From Mechanisms of resistance to EGFR-targeted drugs: lung cancer (2016) · cites this paper as [41]
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- Authors
- Della Corte, C. M., Bellevicine, C., Vicidomini, G., Vitagliano, D., Malapelle, U., Accardo, M., Fabozzi, A., Fiorelli, A., Fasano, M., Papaccio, F., Martinelli, E., Troiani, T., Troncone, G., Santini, M., Bianco, R., Ciardiello, F., & Morgillo, F.
- Affiliations
- 1Oncologia Medica, Dipartimento Medico-Chirurgico di Internistica Clinica e Sperimentale “F. Magrassi e A. Lanzara,” Seconda Università degli Studi di Napoli, Naples, Italy.
- University of Naples Federico II (IT)
- University of Campania "Luigi Vanvitelli" (IT)
- Federico II University Hospital (IT)
- Corresponding author
- Morgillo, Floriana
- ORCID
- Venue
- Clinical Cancer Research
- Published
- 2015-10-14
- Volume
- 21
- Issue
- 20
- Pages
- 4686-4697
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- OpenAlex
- W1938204876
- Cited by
- 122
- References
- 31
- Citations by year
- 2026: 4 · 2025: 4 · 2024: 11 · 2023: 6 · 2022: 8 · 2021: 10 · 2020: 10 · 2019: 15 · 2018: 23 · 2017: 21 · 2016: 8 · 2015: 2
- FWCI
- 14.26
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Clinical Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Archivio Istituzionale della Ricerca - Università degli Studi della Campania "Luigi Vanvitelli" (submittedVersion)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Hedgehog Signaling Pathway Studies
- Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
- Keywords
- Hedgehog signaling, EGFR tyrosine kinase inhibitor resistance, non-small cell lung cancer, epithelial-mesenchymal transition, MET activation, Gli1, EGFR mutation, EGFR wild-type, combination therapy, LDE225, PI3K/Akt signaling, MAPK signaling, chemosensitization
- MeSH terms
- Smoothened Receptor, Animals, Biphenyl Compounds, Carcinoma, Non-Small-Cell Lung, Female, Gene Amplification, Humans, Lung Neoplasms, Mice, Inbred BALB C, Mice, Nude, Pyridines, Signal Transduction, Down-Regulation, Drug Resistance, Neoplasm, Proto-Oncogene Proteins c-met, Phosphatidylinositol 3-Kinases, Receptors, G-Protein-Coupled, Cell Line, Tumor, Protein Kinase Inhibitors, Cell Proliferation, Proto-Oncogene Proteins c-akt, Mice, Hedgehog Proteins, Epithelial-Mesenchymal Transition, ErbB Receptors
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