Cabozantinib and dasatinib synergize to induce tumor regression in non-clear cell renal cell carcinoma.

Cell Reports Medicine
Hui-Wen LueGeorge V Thomas

Abstract

The lack of effective treatment options for advanced non-clear cell renal cell carcinoma (NCCRCC) is a critical unmet clinical need. Applying a high-throughput drug screen to multiple human kidney cancer cells, we identify the combination of the VEGFR-MET inhibitor cabozantinib and the SRC inhibitor dasatinib acts synergistically in cells to markedly reduce cell viability. Importantly, the combination is well tolerated and causes tumor regression in vivo. Transcriptional and phosphoproteomic profiling reveals that the combination converges to downregulate the MAPK-ERK signaling pathway, a result not predicted by single-agent analysis alone. Correspondingly, the addition of a MEK inhibitor synergizes with either dasatinib or cabozantinib to increase its efficacy. This study, by using approved, clinically relevant drugs, provides the rationale for the design of effective combination treatments in NCCRCC that can be rapidly translated to the clinic.

References

Dec 9, 1998·Proceedings of the National Academy of Sciences of the United States of America·M B EisenD Botstein
May 1, 2002·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Robert J MotzerVictor Reuter
Aug 2, 2003·The New England Journal of Medicine·Daniel J George, William G Kaelin
Oct 22, 2003·Journal of the American Society of Nephrology : JASN·William G Kaelin
Dec 19, 2003·Nucleic Acids Research·Rolf ApweilerLai-Su L Yeh
Jun 2, 2004·Nature Reviews. Cancer·Timothy J Yeatman
Jun 8, 2004·Bioinformatics·Alok J Saldanha
Oct 4, 2005·Proceedings of the National Academy of Sciences of the United States of America·Aravind SubramanianJill P Mesirov
Feb 4, 2006·Journal of Biomedical Science·Li MaXueliang Zhu
Nov 4, 2006·Cancer·Ellen A RonnenRobert J Motzer
Jul 8, 2009·Nature Biotechnology·Joseph LehárAlexis A Borisy
Sep 22, 2010·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Faye M JohnsonDavid J Stewart
Jan 25, 2011·Journal of Proteome Research·Jürgen CoxMatthias Mann
Apr 28, 2011·Cancer·Heather D BrooksVassiliki A Papadimitrakopoulou
May 5, 2011·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Keila E TorresDina Lev
May 27, 2011·Cancer Research·Weon-Kyoo YouDonald M McDonald
Jun 3, 2011·Science Translational Medicine·Natsuko SuwakiGeorge V Thomas
Sep 10, 2011·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Erica L MayerAntonio Llombart-Cussac
Feb 7, 2012·Proceedings of the National Academy of Sciences of the United States of America·Justin M DrakeOwen N Witte
Oct 30, 2012·Bioinformatics·Alexander DobinThomas R Gingeras
Sep 11, 2013·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Robert J MotzerThomas E Hutson
Mar 19, 2014·Journal of the National Cancer Institute·Timothy J GrahamSimon P Robinson
Sep 23, 2014·International Journal of Cancer. Journal International Du Cancer·Eun-Kee SongJohn J Arcaroli
Dec 18, 2014·Genome Biology·Michael I LoveSimon Anders
Jan 22, 2015·Nucleic Acids Research·Matthew E RitchieGordon K Smyth
Sep 26, 2015·The New England Journal of Medicine·Toni K ChoueiriUNKNOWN METEOR Investigators
Oct 4, 2015·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Mansoureh SameniBonnie F Sloane
Oct 10, 2015·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Ryan H TakahashiLuna Musib
Nov 5, 2015·The New England Journal of Medicine·W Marston LinehanUNKNOWN Cancer Genome Atlas Research Network
May 22, 2016·Bioinformatics·Zuguang GuMatthias Schlesner
Jul 9, 2016·Journal of Cancer·Zuoquan XieBrian Shuch

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