Abstract
Multikinase inhibitors (MKIs) targeting VEGF receptors and other receptor tyrosine kinases have shown considerable activity in clinical trials of thyroid cancer. Thyroid cancer frequently exhibits activation of the RAS/RAF/MEK/ERK pathway. In other types of cancer, paradoxical ERK activation has emerged as a potential resistance mechanism to RAF-inhibiting drugs including MKIs such as sorafenib and pazopanib. We therefore queried whether the MEK inhibitor trametinib, could augment the activity of pazopanib in thyroid cancer cell lines. Trametinib potently inhibited growth in vitro (GI50 1.1-4.8 nM), whereas pazopanib had more limited in vitro activity, as anticipated (GI50 1.4-7.1 µM). We observed progressive upregulation of ERK activity with pazopanib treatment, an effect abrogated by trametinib. For xenografts (bearing either KRASG12R or BRAFV600E mutations), the combination of trametinib and pazopanib led to sustained shrinkage in tumor volume by 50% or more, compared to pre-treatment baseline. Trametinib also was highly effective as a single agent, compared to pazopanib alone. These preclinical findings support the evaluation of trametinib, alone or in combination with pazopanib or other kinase inhibitors, in thyroid cancer...Continue Reading
References
Jan 1, 1984·Advances in Enzyme Regulation·T C Chou, P Talalay
Oct 7, 2004·Cancer Research·Scott M WilhelmPamela A Trail
Jul 11, 2007·Molecular Cancer Therapeutics·Rakesh KumarMui Cheung
Sep 20, 2007·The Journal of Clinical Endocrinology and Metabolism·Douglas W BallBarry D Nelkin
Apr 3, 2008·The Journal of Clinical Endocrinology and Metabolism·Rebecca LeboeufJames A Fagin
Jun 3, 2009·Cancer Research·Julio C Ricarte-FilhoJames A Fagin
Jun 11, 2009·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Herbert I HurwitzLini Pandite
Jan 27, 2010·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Cora N SternbergRobert E Hawkins
Feb 5, 2010·Nature·Georgia HatzivassiliouShiva Malek
Feb 10, 2010·Cell·Sonja J HeidornRichard Marais
Feb 25, 2010·Nature·Poulikos I PoulikakosNeal Rosen
Jun 29, 2010·Thyroid : Official Journal of the American Thyroid Association·Mingzhao Xing
Sep 21, 2010·The Lancet Oncology·Keith C BibleUNKNOWN Mayo Phase 2 Consortium
Nov 18, 2010·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Brunilde GrilPatricia S Steeg
Jan 20, 2011·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Aidan G GilmartinSylvie G Laquerre
Nov 19, 2011·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Jean Philippe ArnaultCaroline Robert
May 19, 2012·Lancet·Winette T A van der GraafUNKNOWN PALETTE study group
Jun 6, 2012·The New England Journal of Medicine·Keith T FlahertyUNKNOWN METRIC Study Group
Jul 10, 2012·The Journal of Clinical Endocrinology and Metabolism·Keith C BibleUNKNOWN Mayo Clinic Endocrine Malignances Disease Oriented Group
Oct 2, 2012·The New England Journal of Medicine·Keith T FlahertyJeffrey Weber
Nov 17, 2012·Cancer Cell·Piro LitoNeal Rosen
Dec 19, 2012·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Kevin B KimKarl D Lewis
Feb 1, 2013·Cancer Discovery·Cristina Montero-CondeJames A Fagin
Feb 15, 2013·The New England Journal of Medicine·Alan L HoJames A Fagin
Feb 19, 2013·The Lancet Oncology·Paolo A AsciertoReinhard Dummer
Jan 9, 2014·CA: a Cancer Journal for Clinicians·Rebecca SiegelAhmedin Jemal
Citations
Mar 15, 2019·Briefings in Bioinformatics·Yu DingLiangde Xu
Mar 27, 2019·Cancers·Cinzia LanziGiuliana Cassinelli
Apr 26, 2017·British Journal of Cancer·Rachna T ShroffNilofer S Azad
Mar 30, 2017·Scientific Reports·Nobuhiko YokoyamaYukihide Iwamoto
Feb 29, 2020·Medical Oncology·Daniela GentileGuido Bocci
Oct 26, 2018·Molecular Cancer·Shikha SainiBellur S Prabhakar
Jul 5, 2019·International Journal of Molecular Sciences·Livia ManzellaPaolo Vigneri
Apr 6, 2017·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Vivek SubbiahNilofer A Azad
Jun 13, 2019·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Razelle KurzrockNilofer S Azad
Aug 3, 2021·Frontiers in Endocrinology·Tanner FullmerMark Zafereo