Treatment of advanced renal cell carcinoma (RCC) has changed drastically in the past decade. The mTORC1 inhibitors, everolimus and temsirolimus (also known as rapalogs), have been shown to be key drugs for use in first-line treatment1 and pretreated patients.2 Although recent evidence showed they had inferior global efficacy compared with modern immunotherapy3 or new targeted agents,4 approximately 20% of all patients with RCC respond to rapalogs. Furthermore, mTOR inhibitors combined with novel antiangiogenic agents have become a standard of care in pretreated patients,5,6 and ongoing trials are exploring the value of these combinations in first-line treatment (ClinicalTrials.gov identifier: NCT02811861).
Extraordinary responses to mTOR inhibitors have been described in few patients with mutations in TSC1, TSC2, or MTOR.7–9 However, a recent study in RCC showed that not all patients with mTOR-activating mutations responded to hh inhibitors, whereas some without mutations did.10 Additionally, Lim et al11 explored MTOR, TSC1, TSC2, NF1, and PIK3CA mutations in a cohort of 22 patients with different tumors with significant response to everolimus, identifying candidate mutations in only 50%. These studies suggest that additional mechanisms, such as clonal heterogeneity,12,13 modulate response. Thus, understanding of the underlying mechanisms leading to mTOR inhibitor tumor sensitivity is currently incomplete, and additional investigations and cases demonstrating exquisite responses are needed.
This study describes a patient with metastatic clear cell RCC (ccRCC) refractory to multiple lines of anti–vascular endothelial growth factor (VEGF) therapy that, on temsirolimus treatment, exhibited an exceptional clinical response. Multiregional whole-exome sequencing (WES), in vitro functional assessment, and immunohistochemistry (IHC) of the tumor samples identified a novel MTOR mutation acquired early during tumor development as being responsible for the drug sensitivity. The molecular characterization of patients experiencing long responses to rapalogs could help define a subset who would benefit from these drugs.
The authors would like to thank the National Centre for Genomic Analysis personnel, and especially Sergi Beltran and Sophia Derdak, for their excellent support in whole-exome sequencing. They also want to thank the CNIO Flow Cytometry Core Unit and Dolores Martinez for their excellent support and assistance.
The authors have disclosed that they have no financial interests, arrangements, affiliations, or commercial interests with the manufacturers of any products discussed in this article or their competitors.
This study was supported by Projects SAF2015-70820-ERC and SAF2015-64850-R (Spanish Ministry of Economy, Industry and Competitiveness MEIC, co-funded by the European Regional Development Fund ERDF) and by the Instituto de Salud Carlos III (Acción Estratégica en Salud grant number PI13/00622).
See JNCCN.org for supplemental online content.
Hudes G, Carducci M, Tomczak P et al.. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med 2007;356:2271–2281.
Motzer RJ, Escudier B, Oudard S et al.. Phase 3 trial of everolimus for metastatic renal cell carcinoma: final results and analysis of prognostic factors. Cancer 2010;116:4256–4265.
Motzer RJ, Escudier B, McDermott DF et al.. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med 2015;373:1803–1813.
Choueiri TK, Escudier B, Powles T et al.. Cabozantinib versus everolimus in advanced renal-cell carcinoma. N Engl J Med 2015;373:1814–1823.
Motzer RJ, Hutson TE, Glen H et al.. Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial. Lancet Oncol 2015;16:1473–1482.
Motzer RJ, Hutson TE, Ren M et al.. Independent assessment of lenvatinib plus everolimus in patients with metastatic renal cell carcinoma. Lancet Oncol 2016;17:e4–5.
Wagle N, Grabiner BC, Van Allen EM et al.. Activating MTOR mutations in a patient with an extraordinary response on a phase I trial of everolimus and pazopanib. Cancer Discov 2014;4:546–553.
Wagle N, Grabiner BC, Van Allen EM et al.. Response and acquired resistance to everolimus in anaplastic thyroid cancer. N Engl J Med 2014;371:1426–1433.
Kwiatkowski DJ, Choueiri TK, Fay AP et al.. Mutations in TSC1, TSC2, and MTOR are associated with response to rapalogs in patients with metastatic renal cell carcinoma. Clin Cancer Res 2016;22:2445–2452.
Lim SM, Park HS, Kim S et al.. Next-generation sequencing reveals somatic mutations that confer exceptional response to everolimus. Oncotarget 2016;7:10547–10556.
Voss MH, Hakimi AA, Pham CG et al.. Tumor genetic analyses of patients with metastatic renal cell carcinoma and extended benefit from MTOR inhibitor therapy. Clin Cancer Res 2014;20:1955–1964.
Voss MH, Hsieh JJ. Therapeutic guide for mTOuRing through the braided kidney cancer genomic river. Clin Cancer Res 2016;22:2320–2322.
Motzer RJ, Bacik J, Mazumdar M. Prognostic factors for survival of patients with stage IV renal cell carcinoma: Memorial Sloan-Kettering Cancer Center experience. Clin Cancer Res 2004;10:6302S–6303S.
Gerlinger M, Horswell S, Larkin J et al.. Genomic architecture and evolution of clear cell renal cell carcinomas defined by multiregion sequencing. Nat Genet 2014;46:225–233.
Sato T, Nakashima A, Guo L et al.. Single amino-acid changes that confer constitutive activation of MTOR are discovered in human cancer. Oncogene 2010;29:2746–2752.
Grabiner BC, Nardi V, Birsoy K et al.. A diverse array of cancer-associated MTOR mutations are hyperactivating and can predict rapamycin sensitivity. Cancer Discov 2014;4:554–563.
Ghosh AP, Marshall CB, Coric T et al.. Point mutations of the MTOR-RHEB pathway in renal cell carcinoma. Oncotarget 2015;6:17895–17910.
Gerlinger M, Rowan AJ, Horswell S et al.. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med 2012;366:883–892.
Pena-Llopis S, Vega-Rubin-de-Celis S, Liao A et al.. BAP1 loss defines a new class of renal cell carcinoma. Nat Genet 2012;44:751–759.
Kapur P, Pena-Llopis S, Christie A et al.. Effects on survival of BAP1 and PBRM1 mutations in sporadic clear-cell renal-cell carcinoma: a retrospective analysis with independent validation. Lancet Oncol 2013;14:159–167.