Unbiased High-Throughput Drug Combination Pilot Screening Identifies Synergistic Drug Combinations Effective against Patient-Derived and Drug-Resistant Melanoma Cell Lines.

SLAS Discovery
David A ClosePaul A Johnston

Abstract

We describe the development, optimization, and validation of 384-well growth inhibition assays for six patient-derived melanoma cell lines (PDMCLs), three wild type (WT) for BRAF and three with V600E-BRAF mutations. We conducted a pilot drug combination (DC) high-throughput screening (HTS) of 45 pairwise 4×4 DC matrices prepared from 10 drugs in the PDMCL assays: two B-Raf inhibitors (BRAFi), a MEK inhibitor (MEKi), and a methylation agent approved for melanoma; cytotoxic topoisomerase II and DNA methyltransferase chemotherapies; and drugs targeting the base excision DNA repair enzyme APE1 (apurinic/apyrimidinic endonuclease-1/redox effector factor-1), SRC family tyrosine kinases, the heat shock protein 90 (HSP90) molecular chaperone, and histone deacetylases.Pairwise DCs between dasatinib and three drugs approved for melanoma therapy-dabrafenib, vemurafenib, or trametinib-were flagged as synergistic in PDMCLs. Exposure to fixed DC ratios of the SRC inhibitor dasatinib with the BRAFis or MEKis interacted synergistically to increase PDMCL sensitivity to growth inhibition and enhance cytotoxicity independently of PDMCL BRAF status. These DCs synergistically inhibited the growth of mouse melanoma cell lines that either were dabraf...Continue Reading

References

Sep 1, 1976·Proceedings of the National Academy of Sciences of the United States of America·T E CareyL J Old
Jun 5, 1996·Journal of the National Cancer Institute·W R GrecoL Levasseur
Oct 19, 2004·Oncogene·Sarah J Parsons, J Thomas Parsons
Feb 3, 2005·Nature Reviews. Drug Discovery·Curtis T KeithBrent R Stockwell
Apr 1, 2005·Journal of Biomolecular Screening·Martha A O'BrienKeith V Wood
Aug 3, 2006·Nature Reviews. Drug Discovery·Janet E Dancey, Helen X Chen
May 13, 2009·Melanoma Research·Jade HomsiAdil I Daud
Jan 19, 2010·The Oncologist·Jordi RodonRazelle Kurzrock
Jul 31, 2010·Molecular Cancer·Alberto Ocaña, Atanasio Pandiella
Aug 7, 2010·Neoplasia : an International Journal for Oncology Research·Alexey Aleshin, Richard S Finn
Sep 17, 2010·The New England Journal of Medicine·Srdan VerstovsekAyalew Tefferi
Oct 30, 2010·Nature Reviews. Drug Discovery·Shivanni KummarJames H Doroshow
Apr 12, 2011·Analytical Chemistry·Cheong Hoon KwonAli Khademhosseini
Apr 28, 2011·Cancer·Harriet M KlugerMario Sznol
Jun 15, 2011·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Juan Carlos MonteroAtanasio Pandiella
Jan 14, 2012·Neoplasia : an International Journal for Oncology Research·Elisabetta VerganiMonica Rodolfo
Jul 12, 2012·Nature Biotechnology·Bissan Al-LazikaniPaul Workman
Oct 13, 2012·Nature Reviews. Drug Discovery·Gideon BollagPeter Hirth
Feb 19, 2013·Oncogene·L N Kwong, M A Davies
Sep 26, 2013·Nature Reviews. Cancer·Caitriona HolohanPatrick G Johnston
Nov 12, 2013·Trends in Pharmacological Sciences·Lucio TentoriGrazia Graziani
Dec 20, 2013·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Meghna Das Thakur, Darrin D Stuart
Jan 28, 2014·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Helen RizosGeorgina V Long
Jan 29, 2014·Proceedings of the National Academy of Sciences of the United States of America·Lesley A Mathews GrinerCraig J Thomas
Apr 3, 2014·Biochemistry Research International·Mark Voskoboynik, Hendrik-Tobias Arkenau
May 3, 2014·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Christine M Lovly, Alice T Shaw
Jun 2, 2014·Hematology/oncology Clinics of North America·Vikram C Gorantla, John M Kirkwood
Jun 7, 2014·Cancer Immunology Research·Zachary A CooperJennifer A Wargo
Nov 12, 2014·Molecular Cancer Therapeutics·Kristina M IlievaSophia N Karagiannis
Nov 22, 2014·Science·Jennifer A Lo, David E Fisher
Jan 17, 2015·Oncoscience·Alex J EustaceNorma O'Donovan
Feb 11, 2015·The Journal of Investigative Dermatology·Diwakar DavarJohn M Kirkwood
Jun 20, 2015·Cell·UNKNOWN Cancer Genome Atlas Network
Jun 23, 2015·Cancer Treatment Reviews·Olivier Michielin, Christoph Hoeller
Jun 24, 2015·Journal of Chemical Biology·Zhiwei FengBarry Gold
Jul 15, 2015·Journal of Laboratory Automation·Grace Ka Yan ChanJohn G Moffat
Jul 17, 2015·JAMA Oncology·Douglas B Johnson, Jeffrey A Sosman
Jan 15, 2016·Journal of Clinical Medicine Research·Adarsh VennepureddyTerenig Terjanian
Feb 3, 2016·Pigment Cell & Melanoma Research·Tongwu ZhangNicholas K Hayward

❮ Previous
Next ❯

Citations

Oct 26, 2021·Molecular Imaging and Biology : MIB : the Official Publication of the Academy of Molecular Imaging·Michael C BellaviaCarolyn J Anderson

❮ Previous
Next ❯

Software Mentioned

GraphPad Prism
MATLAB
COMPUSYN

Related Concepts

Related Feeds

Apoptosis

Apoptosis is a specific process that leads to programmed cell death through the activation of an evolutionary conserved intracellular pathway leading to pathognomic cellular changes distinct from cellular necrosis