FGFR Inhibition Overcomes Resistance to EGFR-targeted Therapy in Epithelial-like Cutaneous Carcinoma
| العنوان: | FGFR Inhibition Overcomes Resistance to EGFR-targeted Therapy in Epithelial-like Cutaneous Carcinoma |
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| المؤلفون: | Eva González-Suárez, R.M. Penín, Luis Palomero, Ricard Mesia, Noelia Vilariño, Salvador Capella-Gutierrez, Diana Pérez Sidelnikova, Miren Taberna, Laura Lorenzo-Sanz, Josep Oriol Bermejo, Josep M. Piulats, Victoria da Silva-Diz, Purificación Muñoz, Alberto Villanueva, Mattia Bosio, Adrià Bernat-Peguera, Joan Maria Viñals, Juan Navarro-Ventura, Francesc Viñals |
| المصدر: | Clinical Cancer Research r-IGTP. Repositorio Institucional de Producción Científica del Instituto de Investigación Germans Trias i Pujol instname |
| بيانات النشر: | American Association for Cancer Research, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | 0301 basic medicine, Male, Cancer Research, Skin Neoplasms, medicine.medical_treatment, FGFR Inhibition, Cell, Apoptosis, Mice, SCID, medicine.disease_cause, Targeted therapy, 03 medical and health sciences, Mice, 0302 clinical medicine, Gefitinib, Mice, Inbred NOD, medicine, Tumor Cells, Cultured, Animals, Humans, Neoplasms, Glandular and Epithelial, Receptor, Fibroblast Growth Factor, Type 1, Protein Kinase Inhibitors, EGFR inhibitors, Cell Proliferation, Mutation, Chemotherapy, business.industry, Xenograft Model Antitumor Assays, Radiation therapy, ErbB Receptors, Gene Expression Regulation, Neoplastic, 030104 developmental biology, medicine.anatomical_structure, Oncology, Drug Resistance, Neoplasm, 030220 oncology & carcinogenesis, Cancer research, Carcinoma, Squamous Cell, business, medicine.drug |
| الوصف: | Purpose: Recurrent and/or metastatic unresectable cutaneous squamous cell carcinomas (cSCCs) are treated with chemotherapy or radiotherapy, but have poor clinical responses. A limited response (up to 45% of cases) to EGFR-targeted therapies was observed in clinical trials with patients with advanced and metastatic cSCC. Here, we analyze the molecular traits underlying the response to EGFR inhibitors, and the mechanisms responsible for cSCC resistance to EGFR-targeted therapy. Experimental Design: We generated primary cell cultures and patient cSCC–derived xenografts (cSCC-PDXs) that recapitulate the histopathologic and molecular features of patient tumors. Response to gefitinib treatment was tested and gefitinib-resistant (GefR) cSCC-PDXs were developed. RNA sequence analysis was performed in matched untreated and GefR cSCC-PDXs to determine the mechanisms driving gefitinib resistance. Results: cSCCs conserving epithelial traits exhibited strong activation of EGFR signaling, which promoted tumor cell proliferation, in contrast to mesenchymal-like cSCCs. Gefitinib treatment strongly blocked epithelial-like cSCC-PDX growth in the absence of EGFR and RAS mutations, whereas tumors carrying the E545K PIK3CA-activating mutation were resistant to treatment. A subset of initially responding tumors acquired resistance after long-term treatment, which was induced by the bypass from EGFR to FGFR signaling to allow tumor cell proliferation and survival upon gefitinib treatment. Pharmacologic inhibition of FGFR signaling overcame resistance to EGFR inhibitor, even in PIK3CA-mutated tumors. Conclusions: EGFR-targeted therapy may be appropriate for treating many epithelial-like cSCCs without PIK3CA-activating mutations. Combined EGFR- and FGFR-targeted therapy may be used to treat cSCCs that show intrinsic or acquired resistance to EGFR inhibitors. |
| تدمد: | 1078-0432 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::d7f8aaff7179eef9c9650328af5c5338Test https://fundanet.igtp.cat/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=2318Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....d7f8aaff7179eef9c9650328af5c5338 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 10780432 |
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