Exceptional Response to Temsirolimus in a Metastatic Clear Cell Renal Cell Carcinoma With an Early Novel MTOR-Activating Mutation

Authors:
Juan Francisco Rodríguez-Moreno From Oncology Unit, Clara Campal Comprehensive Cancer Center, Madrid, Spain; Spanish Oncology GenitoUrinary Group (SOGUG), Madrid, Spain; Hereditary Endocrine Cancer Group, Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain; Instituto de Biomedicina de Sevilla, IBiS/Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain; Department of Surgery, Whipps Cross Hospital, London, United Kingdom; and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.
From Oncology Unit, Clara Campal Comprehensive Cancer Center, Madrid, Spain; Spanish Oncology GenitoUrinary Group (SOGUG), Madrid, Spain; Hereditary Endocrine Cancer Group, Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain; Instituto de Biomedicina de Sevilla, IBiS/Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain; Department of Surgery, Whipps Cross Hospital, London, United Kingdom; and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.

Search for other papers by Juan Francisco Rodríguez-Moreno in
Current site
Google Scholar
PubMed
Close
 MD
,
María Apellaniz-Ruiz From Oncology Unit, Clara Campal Comprehensive Cancer Center, Madrid, Spain; Spanish Oncology GenitoUrinary Group (SOGUG), Madrid, Spain; Hereditary Endocrine Cancer Group, Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain; Instituto de Biomedicina de Sevilla, IBiS/Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain; Department of Surgery, Whipps Cross Hospital, London, United Kingdom; and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.

Search for other papers by María Apellaniz-Ruiz in
Current site
Google Scholar
PubMed
Close
 PhD
,
Juan María Roldan-Romero From Oncology Unit, Clara Campal Comprehensive Cancer Center, Madrid, Spain; Spanish Oncology GenitoUrinary Group (SOGUG), Madrid, Spain; Hereditary Endocrine Cancer Group, Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain; Instituto de Biomedicina de Sevilla, IBiS/Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain; Department of Surgery, Whipps Cross Hospital, London, United Kingdom; and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.

Search for other papers by Juan María Roldan-Romero in
Current site
Google Scholar
PubMed
Close
 MS
,
Ignacio Durán From Oncology Unit, Clara Campal Comprehensive Cancer Center, Madrid, Spain; Spanish Oncology GenitoUrinary Group (SOGUG), Madrid, Spain; Hereditary Endocrine Cancer Group, Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain; Instituto de Biomedicina de Sevilla, IBiS/Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain; Department of Surgery, Whipps Cross Hospital, London, United Kingdom; and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.

Search for other papers by Ignacio Durán in
Current site
Google Scholar
PubMed
Close
 MD
,
Luis Beltrán From Oncology Unit, Clara Campal Comprehensive Cancer Center, Madrid, Spain; Spanish Oncology GenitoUrinary Group (SOGUG), Madrid, Spain; Hereditary Endocrine Cancer Group, Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain; Instituto de Biomedicina de Sevilla, IBiS/Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain; Department of Surgery, Whipps Cross Hospital, London, United Kingdom; and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.

Search for other papers by Luis Beltrán in
Current site
Google Scholar
PubMed
Close
 MD
,
Cristina Montero-Conde From Oncology Unit, Clara Campal Comprehensive Cancer Center, Madrid, Spain; Spanish Oncology GenitoUrinary Group (SOGUG), Madrid, Spain; Hereditary Endocrine Cancer Group, Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain; Instituto de Biomedicina de Sevilla, IBiS/Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain; Department of Surgery, Whipps Cross Hospital, London, United Kingdom; and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.

Search for other papers by Cristina Montero-Conde in
Current site
Google Scholar
PubMed
Close
 PhD
,
Alberto Cascón From Oncology Unit, Clara Campal Comprehensive Cancer Center, Madrid, Spain; Spanish Oncology GenitoUrinary Group (SOGUG), Madrid, Spain; Hereditary Endocrine Cancer Group, Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain; Instituto de Biomedicina de Sevilla, IBiS/Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain; Department of Surgery, Whipps Cross Hospital, London, United Kingdom; and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.
From Oncology Unit, Clara Campal Comprehensive Cancer Center, Madrid, Spain; Spanish Oncology GenitoUrinary Group (SOGUG), Madrid, Spain; Hereditary Endocrine Cancer Group, Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain; Instituto de Biomedicina de Sevilla, IBiS/Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain; Department of Surgery, Whipps Cross Hospital, London, United Kingdom; and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.

Search for other papers by Alberto Cascón in
Current site
Google Scholar
PubMed
Close
 PhD
,
Mercedes Robledo From Oncology Unit, Clara Campal Comprehensive Cancer Center, Madrid, Spain; Spanish Oncology GenitoUrinary Group (SOGUG), Madrid, Spain; Hereditary Endocrine Cancer Group, Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain; Instituto de Biomedicina de Sevilla, IBiS/Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain; Department of Surgery, Whipps Cross Hospital, London, United Kingdom; and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.
From Oncology Unit, Clara Campal Comprehensive Cancer Center, Madrid, Spain; Spanish Oncology GenitoUrinary Group (SOGUG), Madrid, Spain; Hereditary Endocrine Cancer Group, Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain; Instituto de Biomedicina de Sevilla, IBiS/Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain; Department of Surgery, Whipps Cross Hospital, London, United Kingdom; and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.

Search for other papers by Mercedes Robledo in
Current site
Google Scholar
PubMed
Close
 PhD
,
Jesus García-Donas From Oncology Unit, Clara Campal Comprehensive Cancer Center, Madrid, Spain; Spanish Oncology GenitoUrinary Group (SOGUG), Madrid, Spain; Hereditary Endocrine Cancer Group, Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain; Instituto de Biomedicina de Sevilla, IBiS/Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain; Department of Surgery, Whipps Cross Hospital, London, United Kingdom; and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.
From Oncology Unit, Clara Campal Comprehensive Cancer Center, Madrid, Spain; Spanish Oncology GenitoUrinary Group (SOGUG), Madrid, Spain; Hereditary Endocrine Cancer Group, Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain; Instituto de Biomedicina de Sevilla, IBiS/Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain; Department of Surgery, Whipps Cross Hospital, London, United Kingdom; and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.

Search for other papers by Jesus García-Donas in
Current site
Google Scholar
PubMed
Close
 MD, PhD
, and
Cristina Rodríguez-Antona From Oncology Unit, Clara Campal Comprehensive Cancer Center, Madrid, Spain; Spanish Oncology GenitoUrinary Group (SOGUG), Madrid, Spain; Hereditary Endocrine Cancer Group, Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain; Instituto de Biomedicina de Sevilla, IBiS/Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain; Department of Surgery, Whipps Cross Hospital, London, United Kingdom; and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.
From Oncology Unit, Clara Campal Comprehensive Cancer Center, Madrid, Spain; Spanish Oncology GenitoUrinary Group (SOGUG), Madrid, Spain; Hereditary Endocrine Cancer Group, Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain; Instituto de Biomedicina de Sevilla, IBiS/Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain; Department of Surgery, Whipps Cross Hospital, London, United Kingdom; and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.

Search for other papers by Cristina Rodríguez-Antona in
Current site
Google Scholar
PubMed
Close
 PhD
Restricted access

mTOR pathway inhibitors are important drugs for the treatment of advanced renal cell carcinoma (RCC). However, no valid predictive markers have been identified to guide treatment selection and identify patients who are sensitive to these drugs. Mutations activating the mTOR pathway have been suggested to predict response; however, their predictive value is still unclear. Here, we present the genomic and functional characterization of a patient with metastatic clear cell RCC (ccRCC) who experienced a partial response to temsirolimus after a poor response to 2 previous lines of treatment. At the time of publication, the patient was disease-free 8 years after temsirolimus treatment. Multiregion whole-exome sequencing (WES) on 3 regions of the primary tumor, 1 metastasis, and blood revealed tumor mutations in driver genes in ccRCC: a missense mutation in VHL (p.W88L), a loss-of-function mutation in BAP1 (p.E454Rfs*15), and a novel missense mutation in MTOR (p.Y1974H). The MTOR mutation was present in all tumor regions, with similar allele frequency as the VHL mutation, and in vitro functional assessment of the MTOR variant demonstrated that it increased mTORC1 activity. Consistently, immunohistochemistry in the tumor samples demonstrated increased levels of phospho-S6. In conclusion, multiregion WES identified a novel MTOR mutation acquired early during tumor development as the event leading to a high sensitivity to temsirolimus treatment. This study supports tumor multiregion sequencing to detect truncal mutations in the mTOR pathway to identify patients sensitive to mTOR inhibitors.

These authors contributed equally.

These authors acted as senior authors.

Correspondence: Cristina Rodríguez-Antona, PhD, Spanish National Cancer Research Centre (CNIO), Hereditary Endocrine Cancer Group, Melchor Fernández Almagro 3, 28029 Madrid, Spain. E-mail: crodriguez@cnio.es; Jesus García-Donas, MD, Clara Campal Comprehensive Cancer Center, Oncology Unit, Oña Street 10, 28050 Madrid, Spain. E-mail: jgarciadonas@gmail.com

Supplementary Materials

    • Supplemental Material (PDF 224 KB)
  • Collapse
  • Expand