Mutations in TSC1, TSC2, and MTOR Are Associated with Response to Rapalogs in Patients with Metastatic Renal Cell Carcinoma

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
David J KwiatkowskiSabina Signoretti

Abstract

We examined the hypothesis that mutations in mTOR pathway genes are associated with response to rapalogs in metastatic renal cell carcinoma (mRCC). We studied a cohort of mRCC patients who were treated with mTOR inhibitors with distinct clinical outcomes. Tumor DNA from 79 subjects was successfully analyzed for mutations using targeted next-generation sequencing of 560 cancer genes. Responders were defined as those with partial response (PR) by RECIST v1.0 or stable disease with any tumor shrinkage for 6 months or longer. Nonresponders were defined as those with disease progression during the first 3 months of therapy. Fisher exact test assessed the association between mutation status in mTOR pathway genes and treatment response. Mutations in MTOR, TSC1, or TSC2 were more common in responders, 12 (28%) of 43, than nonresponders, 4 (11%) of 36 (P = 0.06). Mutations in TSC1 or TSC2 alone were also more common in responders, 9 (21%), than nonresponders, 2(6%), (P = 0.05). Furthermore, 5 (42%) of 12 subjects with PR had mutations in MTOR, TSC1, or TSC2 compared with 4 (11%) of 36 nonresponders (P = 0.03). Eight additional non-mTOR pathway genes were found to be mutated in at least 4 of 79 tumors (5%); none were associated positivel...Continue Reading

References

Jun 11, 1999·Genes & Development·A C GingrasN Sonenberg
May 5, 2001·Genome Research·P C Ng, S Henikoff
May 29, 2003·Nature Cell Biology·Yong ZhangDuojia Pan
Jul 19, 2003·Genes & Development·Ken InokiKun-Liang Guan
Oct 12, 2004·Biostatistics·Adam B OlshenMichael Wigler
Jun 1, 2007·The New England Journal of Medicine·Gary HudesUNKNOWN Global ARCC Trial
May 24, 2008·Science·Yasemin SancakDavid M Sabatini
Jun 10, 2009·Bioinformatics·Heng LiUNKNOWN 1000 Genome Project Data Processing Subgroup
Dec 4, 2009·Oncogene·S Menon, B D Manning
Jan 6, 2010·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Andrew J WagnerRobert G Maki
Jan 19, 2010·Bioinformatics·Heng Li, Richard Durbin
Apr 1, 2010·Nature Methods·Ivan A AdzhubeiShamil R Sunyaev
Jan 12, 2011·Nature Biotechnology·James T RobinsonJill P Mesirov
Jul 30, 2011·Molecular Cancer Research : MCR·Blanka KucejovaJames Brugarolas
Feb 11, 2012·Nucleic Acids Research·Yuval Benjamini, Terence P Speed
Mar 9, 2012·The New England Journal of Medicine·Marco GerlingerCharles Swanton
Aug 28, 2012·Science·Gopa IyerDavid B Solit
Aug 29, 2012·International Journal of Cancer. Journal International Du Cancer·Mark A DicksonIzabela A Malinowska
Jun 4, 2013·Nature Cell Biology·Christian C Dibble, Brendan D Manning
Jun 20, 2013·The Journal of Pathology·Simone HettmerAmy J Wagers
Jun 25, 2013·Nature·UNKNOWN Cancer Genome Atlas Research Network
Feb 11, 2014·Cell Metabolism·Jing LiJohn Blenis
Mar 14, 2014·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Martin H VossJames J Hsieh
Jul 22, 2014·Nature·Yinan ZhangBrendan D Manning
Oct 9, 2014·The New England Journal of Medicine·Nikhil WagleJochen H Lorch
Jul 15, 2015·Trends in Cell Biology·Christian C Dibble, Lewis C Cantley

❮ Previous
Next ❯

Citations

Aug 3, 2016·The Journal of Clinical Investigation·Jianing XuJames J Hsieh
Oct 4, 2016·Nature Reviews. Nephrology·Yasser Riazalhosseini, Mark Lathrop
Oct 18, 2016·Pediatric Blood & Cancer·Samara L PotterD Williams Parsons
Dec 17, 2016·International Journal of Molecular Sciences·Veronica RojasLorna Rodriguez-Rodriguez
Sep 8, 2016·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Sumanta K PalNeeraj Agarwal
Mar 10, 2017·Nature Reviews. Disease Primers·James J HsiehVincenzo Ficarra
Jan 26, 2017·The New England Journal of Medicine·Toni K Choueiri, Robert J Motzer
Jul 12, 2017·Nature Reviews. Nephrology·Edwin M PosadasRobert A Figlin
Mar 7, 2018·Nature Reviews. Clinical Oncology·Filip JankuFunda Meric-Bernstam
Sep 30, 2017·CA: a Cancer Journal for Clinicians·Pedro C Barata, Brian I Rini
Sep 27, 2018·PLoS Genetics·Lana HamiehDavid J Kwiatkowski
Aug 5, 2017·Applied Immunohistochemistry & Molecular Morphology : AIMM·Jerzy LasotaMarkku Miettinen
Oct 30, 2018·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Rana R McKayToni K Choueiri
Oct 30, 2018·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·David F McDermott, Michael Carducci
Oct 30, 2018·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·James J HsiehEmily H Cheng
Jan 26, 2018·Current Treatment Options in Oncology·David M GillBenjamin L Maughan
Jan 27, 2019·Expert Review of Anticancer Therapy·Costanza CaninoCamillo Porta
Apr 9, 2019·International Journal of Urology : Official Journal of the Japanese Urological Association·Jun TeishimaAkio Matsubara
Jul 25, 2019·International Journal of Cancer. Journal International Du Cancer·Juan M Roldan-RomeroUNKNOWN Spanish Oncology Genitourinary Group (SOGUG)
Dec 22, 2019·Cancers·Lucía Carril-AjuriaGuillermo de Velasco
Sep 10, 2019·Expert Review of Molecular Diagnostics·Alessia CimadamoreHolger Moch
Oct 28, 2019·Anti-cancer Agents in Medicinal Chemistry·Priyanka VermaIndrakant K Singh
Oct 22, 2016·Clinical and Translational Medicine·James J Hsieh, Emily H Cheng
Jul 7, 2019·Journal of Hematology & Oncology·Hui HuaYangfu Jiang
Aug 21, 2020·The Journal of Pathology·Helén NilssonMartin E Johansson

❮ Previous
Next ❯

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