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Translational Cancer Mechanisms and Therapy

FGFR Inhibition Overcomes Resistance to EGFR-targeted Therapy in Epithelial-like Cutaneous Carcinoma

Adrià Bernat-Peguera, Juan Navarro-Ventura, Laura Lorenzo-Sanz, Victoria da Silva-Diz, Mattia Bosio, Luis Palomero, Rosa M. Penin, Diana Pérez Sidelnikova, Josep Oriol Bermejo, Miren Taberna, Noelia Vilariño, Josep M. Piulats, Ricard Mesia, Joan Maria Viñals, Eva González-Suárez, Salvador Capella-Gutierrez, Alberto Villanueva, Francesc Viñals and Purificación Muñoz
Adrià Bernat-Peguera
1Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain.
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Juan Navarro-Ventura
1Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain.
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  • ORCID record for Juan Navarro-Ventura
Laura Lorenzo-Sanz
1Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain.
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  • ORCID record for Laura Lorenzo-Sanz
Victoria da Silva-Diz
1Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain.
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Mattia Bosio
2Department of Life Sciences, Barcelona Supercomputing Center (BSC), Barcelona, Spain.
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  • ORCID record for Mattia Bosio
Luis Palomero
3Program Against Cancer Therapeutic Resistance (ProCURE), ICO, IDIBELL, Barcelona, Spain.
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  • ORCID record for Luis Palomero
Rosa M. Penin
4Pathology Service, Hospital Universitario de Bellvitge/IDIBELL, Barcelona, Spain.
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Diana Pérez Sidelnikova
5Plastic Surgery Unit, Hospital Universitario de Bellvitge/IDIBELL, Barcelona, Spain.
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Josep Oriol Bermejo
5Plastic Surgery Unit, Hospital Universitario de Bellvitge/IDIBELL, Barcelona, Spain.
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Miren Taberna
6Department of Medical Oncology, Oncobell Program, IDIBELL, ICO, Barcelona, Spain.
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Noelia Vilariño
6Department of Medical Oncology, Oncobell Program, IDIBELL, ICO, Barcelona, Spain.
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Josep M. Piulats
6Department of Medical Oncology, Oncobell Program, IDIBELL, ICO, Barcelona, Spain.
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Ricard Mesia
7Department of Medical Oncology, ICO, B-ARGO Group-Badalona, IGTP, Barcelona, Spain.
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Joan Maria Viñals
5Plastic Surgery Unit, Hospital Universitario de Bellvitge/IDIBELL, Barcelona, Spain.
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Eva González-Suárez
1Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain.
8Molecular Oncology, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
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Salvador Capella-Gutierrez
2Department of Life Sciences, Barcelona Supercomputing Center (BSC), Barcelona, Spain.
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Alberto Villanueva
3Program Against Cancer Therapeutic Resistance (ProCURE), ICO, IDIBELL, Barcelona, Spain.
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Francesc Viñals
3Program Against Cancer Therapeutic Resistance (ProCURE), ICO, IDIBELL, Barcelona, Spain.
9Unitat de Bioquímica i Biologia Molecular, Departament de Ciències Fisiològiques, Universitat de Barcelona-IDIBELL, Barcelona, Spain.
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Purificación Muñoz
1Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain.
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  • For correspondence: p.munoz@idibell.cat
DOI: 10.1158/1078-0432.CCR-20-0232
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Abstract

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.

Footnotes

  • Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).

  • Clin Cancer Res 2020;XX:XX–XX

  • Received January 20, 2020.
  • Revision received October 11, 2020.
  • Accepted November 25, 2020.
  • Published first December 1, 2020.
  • ©2020 American Association for Cancer Research.

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This OnlineFirst version was published on January 13, 2021
doi: 10.1158/1078-0432.CCR-20-0232

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FGFR Inhibition Overcomes Resistance to EGFR-targeted Therapy in Epithelial-like Cutaneous Carcinoma
Adrià Bernat-Peguera, Juan Navarro-Ventura, Laura Lorenzo-Sanz, Victoria da Silva-Diz, Mattia Bosio, Luis Palomero, Rosa M. Penin, Diana Pérez Sidelnikova, Josep Oriol Bermejo, Miren Taberna, Noelia Vilariño, Josep M. Piulats, Ricard Mesia, Joan Maria Viñals, Eva González-Suárez, Salvador Capella-Gutierrez, Alberto Villanueva, Francesc Viñals and Purificación Muñoz
Clin Cancer Res January 13 2021 DOI: 10.1158/1078-0432.CCR-20-0232

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FGFR Inhibition Overcomes Resistance to EGFR-targeted Therapy in Epithelial-like Cutaneous Carcinoma
Adrià Bernat-Peguera, Juan Navarro-Ventura, Laura Lorenzo-Sanz, Victoria da Silva-Diz, Mattia Bosio, Luis Palomero, Rosa M. Penin, Diana Pérez Sidelnikova, Josep Oriol Bermejo, Miren Taberna, Noelia Vilariño, Josep M. Piulats, Ricard Mesia, Joan Maria Viñals, Eva González-Suárez, Salvador Capella-Gutierrez, Alberto Villanueva, Francesc Viñals and Purificación Muñoz
Clin Cancer Res January 13 2021 DOI: 10.1158/1078-0432.CCR-20-0232
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