PMID- 30256787 OWN - NLM STAT- MEDLINE DCOM- 20190116 LR - 20221207 IS - 1553-7404 (Electronic) IS - 1553-7390 (Print) IS - 1553-7390 (Linking) VI - 14 IP - 9 DP - 2018 Sep TI - Mechanisms of acquired resistance to rapalogs in metastatic renal cell carcinoma. PG - e1007679 LID - 10.1371/journal.pgen.1007679 [doi] LID - e1007679 AB - The mechanistic target of rapamycin (mTOR) is an established therapeutic target in renal cell carcinoma (RCC). Mechanisms of secondary resistance to rapalog therapy in RCC have not been studied previously. We identified six patients with metastatic RCC who initially responded to mTOR inhibitor therapy and then progressed, and had pre-treatment and post-treatment tumor samples available for analysis. We performed deep whole exome sequencing on the paired tumor samples and a blood sample. Sequence data was analyzed using Mutect, CapSeg, Absolute, and Phylogic to identify mutations, copy number changes, and their changes over time. We also performed in vitro functional assays on PBRM1 in RCC cell lines. Five patients had clear cell and one had chromophobe RCC. 434 somatic mutations in 416 genes were identified in the 12 tumor samples. 201 (46%) of mutations were clonal in both samples while 129 (30%) were acquired in the post-treatment samples. Tumor heterogeneity or sampling issues are likely to account for some mutations that were acquired in the post-treatment samples. Three samples had mutations in TSC1; one in PTEN; and none in MTOR. PBRM1 was the only gene in which mutations were acquired in more than one post-treatment sample. We examined the effect of PBRM1 loss in multiple RCC cell lines, and could not identify any effect on rapalog sensitivity in in vitro culture assays. We conclude that mTOR pathway gene mutations did not contribute to rapalog resistance development in these six patients with advanced RCC. Furthermore, mechanisms of resistance to rapalogs in RCC remain unclear and our results suggest that PBRM1 loss may contribute to sensitivity through complex transcriptional effects. FAU - Hamieh, Lana AU - Hamieh L AD - Department of Medicine, Brigham and Women's Hospital, Boston, MA, United States of America. AD - Department of Medicine, Harvard Medical School, Boston, MA, United States of America. FAU - Choueiri, Toni K AU - Choueiri TK AUID- ORCID: 0000-0002-9201-3217 AD - Department of Medicine, Brigham and Women's Hospital, Boston, MA, United States of America. AD - Department of Medicine, Harvard Medical School, Boston, MA, United States of America. AD - Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, United States of America. FAU - Ogorek, Barbara AU - Ogorek B AD - Department of Medicine, Brigham and Women's Hospital, Boston, MA, United States of America. AD - Department of Medicine, Harvard Medical School, Boston, MA, United States of America. FAU - Khabibullin, Damir AU - Khabibullin D AD - Department of Medicine, Brigham and Women's Hospital, Boston, MA, United States of America. AD - Department of Medicine, Harvard Medical School, Boston, MA, United States of America. FAU - Rosebrock, Daniel AU - Rosebrock D AD - Cancer Program, Broad Institute of Harvard and MIT, Cambridge, MA, United States of America. FAU - Livitz, Dimitri AU - Livitz D AD - Cancer Program, Broad Institute of Harvard and MIT, Cambridge, MA, United States of America. FAU - Fay, Andre AU - Fay A AD - Department of Medicine, Brigham and Women's Hospital, Boston, MA, United States of America. AD - Department of Medical Oncology, PUCRS School of Medicine, Porto Alegre, Brazil. FAU - Pignon, Jean-Christophe AU - Pignon JC AUID- ORCID: 0000-0002-9627-4078 AD - Department of Medicine, Harvard Medical School, Boston, MA, United States of America. AD - Department of Pathology, Brigham and Women's Hospital, Boston, MA, United States of America. FAU - McDermott, David F AU - McDermott DF AD - Department of Medicine, Harvard Medical School, Boston, MA, United States of America. AD - Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, United States of America. FAU - Agarwal, Neeraj AU - Agarwal N AD - Division of Medical Oncology, University of Utah Huntsman Cancer Institute, Salt Lake City, UT, United States of America. FAU - Gao, Wenhua AU - Gao W AD - Department of Medicine, Brigham and Women's Hospital, Boston, MA, United States of America. AD - Department of Medicine, Harvard Medical School, Boston, MA, United States of America. AD - Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, United States of America. FAU - Signoretti, Sabina AU - Signoretti S AD - Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, United States of America. AD - Department of Pathology, Brigham and Women's Hospital, Boston, MA, United States of America. FAU - Kwiatkowski, David J AU - Kwiatkowski DJ AUID- ORCID: 0000-0002-5668-5219 AD - Department of Medicine, Brigham and Women's Hospital, Boston, MA, United States of America. AD - Department of Medicine, Harvard Medical School, Boston, MA, United States of America. AD - Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, United States of America. LA - eng GR - P50 CA101942/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20180926 PL - United States TA - PLoS Genet JT - PLoS genetics JID - 101239074 RN - 0 (Antineoplastic Agents) RN - 0 (DNA-Binding Proteins) RN - 0 (Nuclear Proteins) RN - 0 (PBRM1 protein, human) RN - 0 (Protein Kinase Inhibitors) RN - 0 (Transcription Factors) RN - 624KN6GM2T (temsirolimus) RN - 9HW64Q8G6G (Everolimus) RN - EC 2.7.1.1 (MTOR protein, human) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - W36ZG6FT64 (Sirolimus) SB - IM MH - Adult MH - Aged MH - Antineoplastic Agents/*pharmacology/therapeutic use MH - Carcinoma, Renal Cell/*drug therapy/genetics/pathology MH - DNA-Binding Proteins MH - Disease Progression MH - Drug Resistance, Neoplasm/*genetics MH - Epigenesis, Genetic MH - Everolimus/pharmacology/therapeutic use MH - Female MH - Gene Expression Regulation, Neoplastic/drug effects MH - Genetic Heterogeneity/drug effects MH - Humans MH - Kidney Neoplasms/*drug therapy/genetics/pathology MH - Male MH - Middle Aged MH - Mutation MH - Nuclear Proteins/*genetics MH - Protein Kinase Inhibitors/*pharmacology/therapeutic use MH - Signal Transduction/genetics MH - Sirolimus/analogs & derivatives/pharmacology/therapeutic use MH - TOR Serine-Threonine Kinases/antagonists & inhibitors/metabolism MH - Transcription Factors/*genetics MH - Exome Sequencing PMC - PMC6181431 COIS- I have read the journal's policy and the authors of this manuscript have the following competing interests: DFM is a consultant/advisory board member for Novartis and Pfizer. DJK is a consultant/advisory board member for Novartis and leads a Novartis-sponsored clinical trial. TKC received research funds from Pfizer, GSK, Novartis, BMS, Merck, Exelixis, Roche, Astra Zeneca, Tracon and is a consultant/advisory board member for Pfizer, GSK, Novartis, Roche, Merck and Bayer. NA is a consultant/advisory board member for Pfizer, Novartis, Merck, Genentech, Eisai, Exelixis, Clovis, EMD Serono, BMS, AstraZeneca, and Astellas. SS received research funds from BMS, Exelixis, AstraZeneca and is a consultant/advisory board member for AstraZeneca and Merck. EDAT- 2018/09/27 06:00 MHDA- 2019/01/17 06:00 PMCR- 2018/09/26 CRDT- 2018/09/27 06:00 PHST- 2018/05/31 00:00 [received] PHST- 2018/09/05 00:00 [accepted] PHST- 2018/10/11 00:00 [revised] PHST- 2018/09/27 06:00 [pubmed] PHST- 2019/01/17 06:00 [medline] PHST- 2018/09/27 06:00 [entrez] PHST- 2018/09/26 00:00 [pmc-release] AID - PGENETICS-D-18-01103 [pii] AID - 10.1371/journal.pgen.1007679 [doi] PST - epublish SO - PLoS Genet. 2018 Sep 26;14(9):e1007679. doi: 10.1371/journal.pgen.1007679. eCollection 2018 Sep.