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Background Parent of origin-specific allelic expression of imprinted genes is epigenetically controlled. In cancer, imprinted genes undergo both genomic and epigenomic alterations, including frequent copy number changes. We investigated whether copy number loss or gain of imprinted genes in cancer cell lines is associated with response to chemotherapy treatment. Results We analyzed 198 human imprinted genes including protein-coding genes and noncoding RNA genes using data from tumor cell lines from the Cancer Cell Line Encyclopedia and Genomics of Drug Sensitivity in Cancer datasets. We examined whether copy number of the imprinted genes in 35 different genome locations was associated with response to cancer drug treatment. We also analyzed associations of pretreatment expression and DNA methylation of imprinted genes with drug response. Higher copy number of BLCAP, GNAS, NNAT, GNAS-AS1, HM13, MIR296, MIR298, and PSIMCT-1 in the chromosomal region 20q11-q13.32 was associated with resistance to multiple antitumor agents. Increased expression of BLCAP and HM13 was also associated with drug resistance, whereas higher methylation of gene regions of BLCAP, NNAT, SGK2, and GNAS was associated with drug sensitivity. While expression and methylation of imprinted genes in several other chromosomal regions was also associated with drug response and many imprinted genes in different chromosomal locations showed a considerable copy number variation, only imprinted genes at 20q11-q13.32 had a consistent association of their copy number with drug response. Copy number values among the imprinted genes in the 20q11-q13.32 region were strongly correlated. They were also correlated with the copy number of cancer-related non-imprinted genes MYBL2, AURKA, and ZNF217 in that chromosomal region. Expression of genes at 20q11-q13.32 was associated with ex vivo drug response in primary tumor samples from the Beat AML 1.0 acute myeloid leukemia patient cohort. Association of the increased copy number of the 20q11-q13.32 region with drug resistance may be complex and could involve multiple genes. Conclusions Copy number of imprinted and non-imprinted genes in the chromosomal region 20q11-q13.32 was associated with cancer drug resistance. The genes in this chromosomal region may have a modulating effect on tumor response to chemotherapy.

Background Indian natural products have been anecdotally used for cancer treatment but with limited efficacy. To better understand their mechanism, we examined the publicly available data for the activity of Indian natural products in the NCI-60 cell line panel. Methods We examined associations of molecular genomic features in the well-characterized NCI-60 cancer cell line panel with in vitro response to treatment with 75 compounds derived from Indian plant-based natural products. We analyzed expression measures for annotated transcripts, lncRNAs, and miRNAs, and protein-changing single nucleotide variants in cancer-related genes. We also examined the similarities between cancer cell line response to Indian natural products and response to reference anti-tumor compounds recorded in a U.S. National Cancer Institute (NCI) Developmental Therapeutics Program database. Results Hierarchical clustering based on cell line response measures identified clustering of Phyllanthus and cucurbitacin products with known anti-tumor agents with anti-mitotic mechanisms of action. Curcumin and curcuminoids mostly clustered together. We found associations of response to Indian natural products with expression of multiple genes, notably including SLC7A11 involved in solute transport and ATAD3A and ATAD3B encoding mitochondrial ATPase proteins, as well as significant associations with functional single nucleotide variants, including BRAF V600E. Conclusion These findings suggest potential mechanisms of action and novel associations of in vitro response with gene expression and some cancer-related mutations that increase our understanding of these Indian natural products.

Natural products provide new opportunities for anticancer chemotherapeutics. We examined the associations of molecular features in the NCI‐60 cancer cell lines with response to 1302 plant, marine, and microbial compounds. Expression or mutations in multiple genes were associated with treatment responses, suggesting potential mechanisms of action of natural compounds. This information will assist in future design of new chemotherapy agents., Natural products remain a significant source of anticancer chemotherapeutics. The search for targeted drugs for cancer treatment includes consideration of natural products, which may provide new opportunities for antitumor cytotoxicity as single agents or in combination therapy. We examined the association of molecular genomic features in the well‐characterized NCI‐60 cancer cell line panel with in vitro response to treatment with 1302 small molecules which included natural products, semisynthetic natural product derivatives, and synthetic compounds based on a natural product pharmacophore from the Developmental Therapeutics Program of the US National Cancer Institute's database. These compounds were obtained from a variety of plant, marine, and microbial species. Molecular information utilized for the analysis included expression measures for 23059 annotated transcripts, lncRNAs, and miRNAs, and data on protein‐changing single nucleotide variants in 211 cancer‐related genes. We found associations of expression of multiple genes including SLFN11, CYP2J2, EPHX1, GPC1, ELF3, and MGMT involved in DNA damage repair, NOTCH family members, ABC and SLC transporters, and both mutations in tyrosine kinases and BRAF V600E with NCI‐60 responses to specific categories of natural products. Hierarchical clustering identified groups of natural products, which correlated with a specific mechanism of action. Specifically, several natural product clusters were associated with SLFN11 gene expression, suggesting that potential action of these compounds may involve DNA damage. The associations between gene expression or genome alterations of functionally relevant genes with the response of cancer cells to natural products provide new information about potential mechanisms of action of these identified clusters of compounds with potentially similar biological effects. This information will assist in future drug discovery and in design of new targeted cancer chemotherapy agents.

PURPOSE: Time is a critical factor in drug action. The duration of inhibition of the target or residence time of the drug molecule on the target often guides drug scheduling. METHODS: The effects of time on the concentration-dependent cytotoxicity of approved and investigational agents [300 compounds] were examined in the NCI60 cell line panel in 2D at 2, 3, 7 and in 3D 11 days. RESULTS: There was a moderate positive linear relationship between data from the 2-day NCI60 screen and the 3-, 7- and 11-day and a strong positive linear relationship between 3-, 7- and 11-day luminescence screen IC(50)s by Pearson correlation analysis. Cell growth inhibition by agents selective for a specific cell cycle phase plateaued when susceptible cells were growth inhibited or killed. As time increased the depth of cell growth inhibition increased without change in the IC(50). DNA interactive agents had decreasing IC(50)s with increasing exposure time. Epigenetic agents required longer exposure times; several were only cytotoxic after 11 days’ exposure. For HDAC inhibitors, time had little or no effect on concentration response. There were potency differences amongst the three BET bromodomain inhibitors tested, and an exposure duration effect. The PARP inhibitors, rucaparib, niraparib, and veliparib reached IC(50)s < 10 μM in some cell lines after 11 days. CONCLUSIONS: The results suggest that variations in compound exposure time may reflect either mechanism of action or com-pound chemical half-life. The activity of slow-acting compounds may optimally be assessed in spheroid models that can be monitored over prolonged incubation times.

Background Altered DNA methylation patterns play important roles in cancer development and progression. We examined whether expression levels of genes directly or indirectly involved in DNA methylation and demethylation may be associated with response of cancer cell lines to chemotherapy treatment with a variety of antitumor agents. Results We analyzed 72 genes encoding epigenetic factors directly or indirectly involved in DNA methylation and demethylation processes. We examined association of their pretreatment expression levels with methylation beta-values of individual DNA methylation probes, DNA methylation averaged within gene regions, and average epigenome-wide methylation levels. We analyzed data from 645 cancer cell lines and 23 cancer types from the Cancer Cell Line Encyclopedia and Genomics of Drug Sensitivity in Cancer datasets. We observed numerous correlations between expression of genes encoding epigenetic factors and response to chemotherapeutic agents. Expression of genes encoding a variety of epigenetic factors, including KDM2B, DNMT1, EHMT2, SETDB1, EZH2, APOBEC3G, and other genes, was correlated with response to multiple agents. DNA methylation of numerous target probes and gene regions was associated with expression of multiple genes encoding epigenetic factors, underscoring complex regulation of epigenome methylation by multiple intersecting molecular pathways. The genes whose expression was associated with methylation of multiple epigenome targets encode DNA methyltransferases, TET DNA methylcytosine dioxygenases, the methylated DNA-binding protein ZBTB38, KDM2B, SETDB1, and other molecular factors which are involved in diverse epigenetic processes affecting DNA methylation. While baseline DNA methylation of numerous epigenome targets was correlated with cell line response to antitumor agents, the complex relationships between the overlapping effects of each epigenetic factor on methylation of specific targets and the importance of such influences in tumor response to individual agents require further investigation. Conclusions Expression of multiple genes encoding epigenetic factors is associated with drug response and with DNA methylation of numerous epigenome targets that may affect response to therapeutic agents. Our findings suggest complex and interconnected pathways regulating DNA methylation in the epigenome, which may both directly and indirectly affect response to chemotherapy.

Background Small cell lung cancer (SCLC) is an aggressive neuroendocrine lung cancer. SCLC progression and treatment resistance involve epigenetic processes. However, links between SCLC DNA methylation and drug response remain unclear. We performed an epigenome-wide study of 66 human SCLC cell lines using the Illumina Infinium MethylationEPIC BeadChip array. Correlations of SCLC DNA methylation and gene expression with in vitro response to 526 antitumor agents were examined. Results We found multiple significant correlations between DNA methylation and chemosensitivity. A potentially important association was observed for TREX1, which encodes the 3′ exonuclease I that serves as a STING antagonist in the regulation of a cytosolic DNA-sensing pathway. Increased methylation and low expression of TREX1 were associated with the sensitivity to Aurora kinase inhibitors AZD-1152, SCH-1473759, SNS-314, and TAK-901; the CDK inhibitor R-547; the Vertex ATR inhibitor Cpd 45; and the mitotic spindle disruptor vinorelbine. Compared with cell lines of other cancer types, TREX1 had low mRNA expression and increased upstream region methylation in SCLC, suggesting a possible relationship with SCLC sensitivity to Aurora kinase inhibitors. We also identified multiple additional correlations indicative of potential mechanisms of chemosensitivity. Methylation of the 3′UTR of CEP350 and MLPH, involved in centrosome machinery and microtubule tracking, respectively, was associated with response to Aurora kinase inhibitors and other agents. EPAS1 methylation was associated with response to Aurora kinase inhibitors, a PLK-1 inhibitor and a Bcl-2 inhibitor. KDM1A methylation was associated with PLK-1 inhibitors and a KSP inhibitor. Increased promoter methylation of SLFN11 was correlated with resistance to DNA damaging agents, as a result of low or no SLFN11 expression. The 5′ UTR of the epigenetic modifier EZH2 was associated with response to Aurora kinase inhibitors and a FGFR inhibitor. Methylation and expression of YAP1 were correlated with response to an mTOR inhibitor. Among non-neuroendocrine markers, EPHA2 was associated with response to Aurora kinase inhibitors and a PLK-1 inhibitor and CD151 with Bcl-2 inhibitors. Conclusions Multiple associations indicate potential epigenetic mechanisms affecting SCLC response to chemotherapy and suggest targets for combination therapies. While many correlations were not specific to SCLC lineages, several lineage markers were associated with specific agents.

The SCLC combination screen examined a 9‐point concentration response of 180 third agents, alone and in combination with etoposide/carboplatin. The predominant effect of adding a third agent to etoposide/carboplatin was additivity. Less than additive effects occurred frequently in SCLC lines sensitive to etoposide/carboplatin. In SCLC lines with little or no response to etoposide/carboplatin, greater than additive SCLC killing occurred over the entire spectrum of SCLC lines but never occurred in all SCLC lines. Exposing SCLC lines to tubulin‐targeted agents (paclitaxel or vinorelbine) simultaneously with etoposide/carboplatin resulted primarily in less than additive cell killing. As single agents, nuclear kinase inhibitors including Aurora kinase inhibitors, Kinesin Spindle Protein/EG5 inhibitors, and Polo‐like kinase‐1 inhibitors were potent cytotoxic agents in SCLC lines; however, simultaneous exposure of the SCLC lines to these agents along with etoposide/carboplatin, generally, resulted in less than additive cell killing. Several classes of agents enhanced the cytotoxicity of etoposide/carboplatin toward the SCLC lines. Exposure of the SCLC lines to the MDM2 inhibitor JNJ‐27291199 produced enhanced killing in 80% of the SCLC lines. Chk‐1 inhibitors such as rabusertib increased the cytotoxicity of etoposide/carboplatin to the SCLC lines in an additive to greater than additive manner. The combination of GSK‐3β inhibitor LY‐2090314 with etoposide/carboplatin increased killing in approximately 40% of the SCLC lines. Exposure to the BET bromodomain inhibitor MK‐8628 increased the SCLC cell killing by etoposide/carboplatin in 20–25% of the SCLC lines. Only 10–15% of the SCLC lines had an increased response to etoposide/carboplatin when simultaneously exposed to the PARP inhibitor talazoparib.

Folate-mediated one-carbon metabolism is essential for growth and survival of cancer cells. We investigated whether the response of cancer cells to antitumor treatment may be partially influenced by variation in expression of one-carbon metabolism genes. We used cancer cell line information from the Cancer Cell Line Encyclopedia and the Genomics of Drug Sensitivity in Cancer resources to examine whether variation in pretreatment expression of one-carbon metabolism-related genes was associated with response to treatment. GART, TYMS, SHMT2, MTR, ALDH2, BHMT, MAT2B, MTHFD2, NNMT, and SLC46A1 showed modest statistically significant correlations with response to a variety of antitumor agents. Higher expression levels of SLC46A1 were associated with resistance to multiple agents, whereas elevated expression of GART, TYMS, SHMT2, MTR, BHMT, and MAT2B was associated with chemosensitivity to multiple drugs. NNMT expression was bimodally distributed and showed different directions of association with various agents. Correlation of increased NNMT expression with sensitivity to dasatinib was validated in the NCI-60 cancer cell line panel. Pretreatment expression levels were correlated among many one-carbon metabolism genes. Expression of several folate genes was strongly associated with expression of multiple components of drug target pathways. Molecular mechanisms underlying associations of one-carbon metabolism gene with drug response require further investigation.

The intracellular effects and overall efficacies of anticancer therapies can vary significantly by tumor type. To identify patterns of drug-induced gene modulation that occur in different cancer cell types, we measured gene-expression changes across the NCI-60 cell line panel after exposure to 15 anticancer agents. The results were integrated into a combined database and set of interactive analysis tools, designated the NCI Transcriptional Pharmacodynamics Workbench (NCI TPW), that allows exploration of gene-expression modulation by molecular pathway, drug target, and association with drug sensitivity. We identified common transcriptional responses across agents and cell types and uncovered gene-expression changes associated with drug sensitivity. We also demonstrated the value of this tool for investigating clinically relevant molecular hypotheses and identifying candidate biomarkers of drug activity. The NCI TPW, publicly available at https://tpwb.nci.nih.gov, provides a comprehensive resource to facilitate understanding of tumor cell characteristics that define sensitivity to commonly used anticancer drugs. Significance: The NCI Transcriptional Pharmacodynamics Workbench represents the most extensive compilation to date of directly measured longitudinal transcriptional responses to anticancer agents across a thoroughly characterized ensemble of cancer cell lines.

Background The APOBEC gene family of cytidine deaminases plays important roles in DNA repair and mRNA editing. In many cancers, APOBEC3B increases the mutation load, generating clusters of closely spaced, single-strand-specific DNA substitutions with a characteristic hypermutation signature. Some studies also suggested a possible involvement of APOBEC3A, REV1, UNG, and FHIT in molecular processes affecting APOBEC mutagenesis. It is important to understand how mutagenic processes linked to the activity of these genes may affect sensitivity of cancer cells to treatment. Results We used information from the Cancer Cell Line Encyclopedia and the Genomics of Drug Sensitivity in Cancer resources to examine associations of the prevalence of APOBEC-like motifs and mutational loads with expression of APOBEC3A, APOBEC3B, REV1, UNG, and FHIT and with cell line chemosensitivity to 255 antitumor drugs. Among the five genes, APOBEC3B expression levels were bimodally distributed, whereas expression of APOBEC3A, REV1, UNG, and FHIT was unimodally distributed. The majority of the cell lines had low levels of APOBEC3A expression. The strongest correlations of gene expression levels with mutational loads or with measures of prevalence of APOBEC-like motif counts and kataegis clusters were observed for REV1, UNG, and APOBEC3A. Sensitivity or resistance of cell lines to JQ1, palbociclib, bicalutamide, 17-AAG, TAE684, MEK inhibitors refametinib, PD-0325901, and trametinib and a number of other agents was correlated with candidate gene expression levels or with abundance of APOBEC-like motif clusters in specific cancers or across cancer types. Conclusions We observed correlations of expression levels of the five candidate genes in cell line models with sensitivity to cancer drug treatment. We also noted suggestive correlations between measures of abundance of APOBEC-like sequence motifs with drug sensitivity in small samples of cell lines from individual cancer categories, which require further validation in larger datasets. Molecular mechanisms underlying the links between the activities of the products of each of the five genes, the resulting mutagenic processes, and sensitivity to each category of antitumor agents require further investigation.

Background Aberrant patterns of DNA methylation are abundant in cancer, and epigenetic pathways are increasingly being targeted in cancer drug treatment. Genetic components of the folate-mediated one-carbon metabolism pathway can affect DNA methylation and other vital cell functions, including DNA synthesis, amino acid biosynthesis, and cell growth. Results We used a bioinformatics tool, the Transcriptional Pharmacology Workbench, to analyze temporal changes in gene expression among epigenetic regulators of DNA methylation and demethylation, and one-carbon metabolism genes in response to cancer drug treatment. We analyzed gene expression information from the NCI-60 cancer cell line panel after treatment with five antitumor agents, 5-azacytidine, doxorubicin, vorinostat, paclitaxel, and cisplatin. Each antitumor agent elicited concerted changes in gene expression of multiple pathway components across the cell lines. Expression changes of FOLR2, SMUG1, GART, GADD45A, MBD1, MTR, MTHFD1, and CTH were significantly correlated with chemosensitivity to some of the agents. Among many genes with concerted expression response to individual antitumor agents were genes encoding DNA methyltransferases DNMT1, DNMT3A, and DNMT3B, epigenetic and DNA repair factors MGMT, GADD45A, and MBD1, and one-carbon metabolism pathway members MTHFD1, TYMS, DHFR, MTR, MAT2A, SLC19A1, ATIC, and GART. Conclusions These transcriptional changes are likely to influence vital cellular functions of DNA methylation and demethylation, cellular growth, DNA biosynthesis, and DNA repair, and some of them may contribute to cytotoxic and apoptotic action of the drugs. This concerted molecular response was observed in a time-dependent manner, which may provide future guidelines for temporal selection of genetic drug targets for combination drug therapy treatment regimens. Electronic supplementary material The online version of this article (doi:10.1186/s13148-016-0240-3) contains supplementary material, which is available to authorized users.