Abstract
The aim of combination drug treatment in cancer therapy is to improve response rate and to decrease the probability of the development of drug resistance. Preferably, drug combinations are synergistic rather than additive, and, ideally, drug combinations work synergistically only in cancer cells and not in non-malignant cells. We have developed a workflow to identify such targeted synergies, and applied this approach to selectively inhibit the proliferation of cell lines with mutations in genes that are difficult to modulate with small molecules. The approach is based on curve shift analysis, which we demonstrate is a more robust method of determining synergy than combination matrix screening with Bliss-scoring. We show that the MEK inhibitor trametinib is more synergistic in combination with the BRAF inhibitor dabrafenib than with vemurafenib, another BRAF inhibitor. In addition, we show that the combination of MEK and BRAF inhibitors is synergistic in BRAF-mutant melanoma cells, and additive or antagonistic in, respectively, BRAF-wild type melanoma cells and non-malignant fibroblasts. This combination exemplifies that synergistic action of drugs can depend on cancer genotype. Next, we used curve shift analysis to identify new drug combinations that specifically inhibit cancer cell proliferation driven by difficult-to-drug cancer genes. Combination studies were performed with compounds that as single agents showed preference for inhibition of cancer cells with mutations in either the CTNNB1 gene (coding for β-catenin), KRAS, or cancer cells expressing increased copy numbers of MYC. We demonstrate that the Wnt-pathway inhibitor ICG-001 and trametinib acted synergistically in Wnt-pathway-mutant cell lines. The ERBB2 inhibitor TAK-165 was synergistic with trametinib in KRAS-mutant cell lines. The EGFR/ERBB2 inhibitor neratinib acted synergistically with the spindle poison docetaxel and with the Aurora kinase inhibitor GSK-1070916 in cell lines with MYC amplification. Our approach can therefore efficiently discover novel drug combinations that selectively target cancer genes.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Combined Chemotherapy Protocols / pharmacology*
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Aza Compounds / administration & dosage
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Aza Compounds / pharmacology
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Benzimidazoles / administration & dosage
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Benzimidazoles / pharmacology
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Cell Line, Tumor / drug effects
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Cell Proliferation / drug effects
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Humans
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Imidazoles / administration & dosage
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Imidazoles / pharmacology
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Indazoles / administration & dosage
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Indazoles / pharmacology
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Indoles / administration & dosage
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Indoles / pharmacology
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Melanoma / drug therapy
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Melanoma / genetics
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Melanoma / pathology
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Molecular Targeted Therapy / methods*
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Mutation
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Oxazoles / administration & dosage
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Oxazoles / pharmacology
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Oximes / administration & dosage
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Oximes / pharmacology
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Proto-Oncogene Proteins B-raf / antagonists & inhibitors
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Proto-Oncogene Proteins B-raf / genetics
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Proto-Oncogene Proteins B-raf / metabolism
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Proto-Oncogene Proteins c-myc / genetics*
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Proto-Oncogene Proteins c-myc / metabolism
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Proto-Oncogene Proteins p21(ras) / genetics*
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Proto-Oncogene Proteins p21(ras) / metabolism
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Pyridones / administration & dosage
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Pyridones / pharmacology
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Pyrimidinones / administration & dosage
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Pyrimidinones / pharmacology
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Quinolines / administration & dosage
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Quinolines / pharmacology
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Sulfonamides / administration & dosage
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Sulfonamides / pharmacology
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Triazoles / administration & dosage
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Triazoles / pharmacology
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Vemurafenib
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beta Catenin / genetics*
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beta Catenin / metabolism
Substances
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2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine
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AZD 6244
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Aza Compounds
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Benzimidazoles
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CTNNB1 protein, human
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GSK 1070916
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Imidazoles
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Indazoles
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Indoles
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KRAS protein, human
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MYC protein, human
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Oxazoles
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Oximes
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Proto-Oncogene Proteins c-myc
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Pyridones
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Pyrimidinones
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Quinolines
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Sulfonamides
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TAK-165
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Triazoles
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beta Catenin
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Vemurafenib
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trametinib
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BRAF protein, human
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Proto-Oncogene Proteins B-raf
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Proto-Oncogene Proteins p21(ras)
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neratinib
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dabrafenib
Grants and funding
This research was supported by a grant from the Innovation Office of the Ministry of Economic Affairs of the Netherlands (INT 111039). Netherlands Translational Research Center B. V. provided support in the form of salaries for authors JCNU, JADMR, AMVD, MBWP, JAPSH, JDM, RCB and GJRZ, but did not have any additional role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.