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.
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