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

被引:4
作者
Close, David A. [1 ]
Kirkwood, John M. [2 ,3 ,4 ,5 ,6 ]
Fecek, Ronald J. [7 ]
Storkus, Walter J. [3 ,6 ,7 ,8 ,9 ,10 ]
Johnston, Paul A. [1 ,6 ]
机构
[1] Univ Pittsburgh, Sch Pharm, Dept Pharmaceut Sci, Room 4101 Pittsburgh Technol Ctr,700 Technol Dr, Pittsburgh, PA 15219 USA
[2] Univ Pittsburgh, Sch Med, Dept Med, Pittsburgh, PA 15213 USA
[3] Univ Pittsburgh, Sch Med, Dept Dermatol, Pittsburgh, PA 15261 USA
[4] Univ Pittsburgh, Sch Med, Dept Translat Sci, Pittsburgh, PA USA
[5] Univ Pittsburgh, Sch Med, Melanoma & Skin Canc Program, Pittsburgh, PA USA
[6] Univ Pittsburgh, Med Ctr, Hillman Canc Ctr, Pittsburgh, PA USA
[7] Lake Erie Coll Osteopath Med Seton Hill, Dept Microbiol, Greensburg, PA USA
[8] Univ Pittsburgh, Sch Med, Dept Immunol, Pittsburgh, PA USA
[9] Univ Pittsburgh, Sch Med, Dept Bioengn, Pittsburgh, PA USA
[10] Univ Pittsburgh, Sch Med, Dept Pathol, Pittsburgh, PA USA
关键词
melanoma; drug combinations; cancer drug resistance; synergy; apoptosis; BRAF INHIBITOR RESISTANCE; SRC FAMILY KINASES; THERAPEUTIC AGENTS; CANCER; THERAPIES; MECHANISMS; DASATINIB; ASSAYS; ACTIVATION; LANDSCAPE;
D O I
10.1177/2472555220970917
中图分类号
Q5 [生物化学];
学科分类号
071010 ; 081704 ;
摘要
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 4x4 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 dabrafenib-sensitive or had acquired resistance to dabrafenib with cross resistance to vemurafenib, trametinib, and dasatinib. Dasatinib DCs with dabrafenib, vemurafenib, or trametinib activated apoptosis and increased cell death in melanoma cells independently of their BRAF status or their drug resistance phenotypes. These preclinical in vitro studies provide a data-driven rationale for the further investigation of DCs between dasatinib and BRAFis or MEKis as candidates for melanoma combination therapies with the potential to improve outcomes and/or prevent or delay the emergence of disease resistance.
引用
收藏
页码:712 / 729
页数:18
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