• dna damage and repair
• protein-protein interaction networks

• Gemcitabine
• Deoxycytidine/analogs & derivatives
• Deoxycytidine/pharmacology
• DNA Repair/drug effects
• Proteomics/methods
• Humans
• Drug Resistance, Neoplasm/genetics
• Drug Resistance, Neoplasm/drug effects
• Cell Line, Tumor
• DNA Damage/drug effects
• Antimetabolites, Antineoplastic/pharmacology
• Signal Transduction/drug effects
• Apoptosis/drug effects
• DNA Replication/drug effects
• Ataxia Telangiectasia Mutated Proteins/metabolism
• Ataxia Telangiectasia Mutated Proteins/antagonists & inhibitors
• Mass Spectrometry/methods

• NRF-CRP22-2019-0003 National Research Foundation Singapore (National Research Foundation-Prime Minister's office, Republic of Singapore)
• Knut och Alice Wallenbergs Stiftelse (Knut and Alice Wallenberg Foundation)
• Singapore Ministry of Education

• Anti-tumour immune response
• Breast cancer
• Connexins
• Exosomes
• Extracellular vesicles
• Gap junctions
• Mammary carcinoma
• Tunelling nanotubes

• Humans
• Connexins/metabolism
• Breast Neoplasms/pathology
• Breast Neoplasms/metabolism
• Cell Communication
• Female
• Gap Junctions/metabolism
• Tumor Microenvironment
• Animals
• Signal Transduction

• c-Src
• carcinogenesis
• drug resistance
• signal transduction
• v-Src

• P20 GM103434 NIGMS NIH HHS
• R15 DE032063 NIDCR NIH HHS
• R15DE032063, P20GM103434 NIH HHS

• Cancer
• Connexins
• Epithelial–mesenchymal transition
• Gap junctions
• Post-translational modification

• Humans
• Connexins/metabolism
• Connexins/pharmacology
• Gap Junctions/metabolism
• Neoplasms/metabolism

• B16F10
• Ras pathway
• cancer
• cell lines
• chemotherapy
• drug resistance
• histone deacetylase 2
• melanoma
• model
• phosphoproteomics

• Aberrant signaling
• Cancer
• Cross-resistance
• Drug resistance
• Therapeutics

• Cirrhosis
• Connexins
• Gap junctions
• Hemichannels
• Intercellular communication
• Liver

The radiation-induced bystander effect (RIBE) can increase cellular toxicity in a gap junction dependent manner in unirradiated bystander cells. Recent reports have suggested that cisplatin toxicity can also be mediated by functional gap junction intercellular communication (GJIC). In this study using lung and ovarian cancer cell lines, we showed that cisplatin cytotoxicity is mediated by cellular density. This effect is ablated when GJA1 or Connexin 43 (Cx43) is targeted, a gap junction gene and protein, respectively, leading to cisplatin resistance but only at high or gap junction forming density. We also observed that the cisplatin-mediated bystander effect was elicited as DNA Double Strand Breaks (DSBs) with positive H2AX Ser139 phosphorylation (γH2AX) formation, an indicator of DNA DSBs. These DSBs are not observed when gap junction formation is prevented. We next showed that cisplatin is not the “death” signal traversing the gap junctions by utilizing the cisplatin-GG intrastrand adduct specific antibody. Finally, we also showed that cells deficient in the structure-specific DNA endonuclease ERCC1-ERCC4 (ERCC1-XPF), an important mediator of cisplatin resistance, further sensitized when treated with cisplatin in the presence of gap junction forming density. Taken together, these results demonstrate the positive effect of GJIC on increasing cisplatin cytotoxicity.

• ERCC1-XPF
• bystander effect
• chemoresistance
• cisplatin
• connexin 43
• gap junction
• gap junction intercellular communication

• bystander effect
• drug resistance
• exosomes
• extracellular vesicles
• tumour microenvironment

• connexins
• gap junctions
• post-translational modifications
• trafficking
• transcription
• translation

• Animals
• Connexins/genetics
• Connexins/metabolism
• Gap Junctions/genetics
• Gap Junctions/metabolism
• Gap Junctions/pathology
• Genetic Diseases, Inborn/genetics
• Genetic Diseases, Inborn/metabolism
• Humans
• Protein Processing, Post-Translational
• Protein Transport

• F31 HL139109 NHLBI NIH HHS
• R01 AA025854 NIAAA NIH HHS
• R01 HL116958 NHLBI NIH HHS
• R01 HL137112 NHLBI NIH HHS

• Cbp-Csk-Src cascade
• DNA repair proteins
• P-glycoprotein
• multidrug resistance

• cancer
• gap junctions
• connexins
• mimetic peptides
• inflammation

• Animals
• Biomarkers
• Bystander Effect/drug effects
• Cell Communication/drug effects
• Gap Junctions/drug effects
• Gap Junctions/metabolism
• Gap Junctions/pathology
• Gene Expression Regulation/drug effects
• Humans
• Inflammation/diagnosis
• Inflammation/etiology
• Inflammation/metabolism
• Inflammation/therapy
• Signal Transduction/drug effects

Clinical responses to anti-cancer therapies often only benefit a defined subset of patients. Predicting the best treatment strategy hinges on our ability to effectively translate genomic data into actionable information on drug responses.

To achieve this goal, we compiled a comprehensive collection of baseline cancer genome data and drug response information derived from a large panel of cancer cell lines. This data set was applied to identify the signature genes relevant to drug sensitivity and their resistance by integrating CNVs and the gene expression of cell lines with in vitro drug responses. We presented an efficient in-silico pipeline for integrating heterogeneous cell line data sources with the simultaneous modeling of drug response values across all the drugs and cell lines. Potential signature genes correlated with drug response (sensitive or resistant) in different cancer types were identified. Using signature genes, our collaborative filtering-based drug response prediction model outperformed the 44 algorithms submitted to the DREAM competition on breast cancer cells. The functions of the identified drug response related signature genes were carefully analyzed at the pathway level and the synthetic lethality level. Furthermore, we validated these signature genes by applying them to the classification of the different subtypes of the TCGA tumor samples, and further uncovered their in vivo implications using clinical patient data.

Our work may have promise in translating genomic data into customized marker genes relevant to the response of specific drugs for a specific cancer type of individual patients.

• cancer cell line
• drug resistance
• drug response
• drug sensitivity
• personalized treatment

Gap junctions (GJs) play an important role in the regulation of cell response to many drugs. However, little is known about their mechanisms. Using an in vitro model of cytotoxicity induced by geneticin (G418), we explored the potential signalling mechanisms involved. Incubation of cells with G418 resulted in cell death, as indicated by the change in cell morphology, loss of cell viability and activation of caspase-3. Before the onset of cell injury, G418 induced reactive oxygen species (ROS) generation, activated oxidative sensitive kinase P38 and caused a shift of connexin 43 (Cx43) from non-phosphorylated form to hyperphosphorylated form. These changes were largely prevented by antioxidants, suggesting an implication of oxidative stress. Downregulation of Cx43 with inhibitors or siRNA suppressed the expression of thioredoxin-interacting protein (TXNIP), activated Akt and protected cells against the toxicity of G418. Further analysis revealed that inhibition of TXNIP with siRNA activated Akt and reproduced the protective effect of Cx43-inhibiting agents, whereas suppression of Akt sensitized cells to the toxicity of G418. Furthermore, interference of TXNIP/Akt also affected puromycin- and adriamycin-induced cell injury. Our study thus characterized TXNIP as a presently unrecognized molecule implicated in the regulatory actions of Cx43 on oxidative drug injury. Targeting Cx43/TXNIP/Akt signalling cascade might be a promising approach to modulate cell response to drugs.

• Akt
• TXNIP
• connexin 43
• cytotoxicity
• gap junction
• oxidative stress

In attempts to develop an orally applicable platinum-based drug, platinum(IV) drugs which exhibit higher in vivo stability compared to the platinum(II) drug cisplatin were formulated. The first such chemotherapeutic agent, namely satraplatin, failed to receive approval. In the present work, we checked the initial cellular stress response of the chemosensitive NCI-H526 small cell lung cancer (SCLC) cells by determination of the relative phosphorylation of 46 specific phosphorylation sites of 38 selected proteins in a six hours response to cisplatin (platinum(II)) or oxoplatin (platinum(IV)), respectively. Oxoplatin is considered as prodrug of cisplatin, although several findings point to differences in intracellular effects. Cisplatin induced hyperphosphorylation of p38α MAPK and AMPKα1, whereas oxoplatin treatment resulted in increased phosphorylation of a large number of signaling proteins involved in stress response/drug resistance, including JNK, GSK-3α, AMPKα1, src kinases, STATs, CHK-2 and especially focal adhesion kinase (FAK). Cisplatin exerts markedly higher cytotoxicity upon four hours short-term exposure in comparison to oxoplatin and, correspondingly, the extended initial stress response to the platinum(IV) drug oxoplatin thus is expected to increase clinical drug resistance. Induction of a substantial stress response to any prodrug of a platinum-based compound may likewise limit the effectivity of its active metabolite(s), such contributing to the failure of selected derivatized platinum complexes.

• ovarian carcinoma
• mucinous
• src kinase
• tubulin
• kx-01

• Acetamides/pharmacology
• Acetamides/therapeutic use
• Adenocarcinoma, Mucinous/drug therapy
• Adenocarcinoma, Mucinous/metabolism
• Adenocarcinoma, Mucinous/pathology
• Animals
• Antineoplastic Agents/pharmacology
• Antineoplastic Agents/therapeutic use
• Apoptosis
• Cell Cycle
• Cell Line, Tumor
• Cell Proliferation/drug effects
• Cell Survival/drug effects
• Drug Synergism
• Female
• Humans
• Inhibitory Concentration 50
• Mice
• Mice, Nude
• Microtubules/metabolism
• Morpholines
• Organoplatinum Compounds/pharmacology
• Organoplatinum Compounds/therapeutic use
• Ovarian Neoplasms/drug therapy
• Ovarian Neoplasms/metabolism
• Ovarian Neoplasms/pathology
• Oxaliplatin
• PTEN Phosphohydrolase/metabolism
• Protein Multimerization
• Pyridines/pharmacology
• Pyridines/therapeutic use
• Tubulin Modulators/pharmacology
• Tubulin Modulators/therapeutic use
• Tumor Burden/drug effects
• Xenograft Model Antitumor Assays
• src-Family Kinases/antagonists & inhibitors
• src-Family Kinases/metabolism

• P30 CA016672 NCI NIH HHS
• P50CA098258 NCI NIH HHS
• CA16672 NCI NIH HHS
• R01 CA109298 NCI NIH HHS
• P50 CA098258 NCI NIH HHS
• U54 CA151668 NCI NIH HHS
• CA098258 NCI NIH HHS
• P50 CA083639 NCI NIH HHS
• R01 CA128797 NCI NIH HHS
• T32 CA009666 NCI NIH HHS
• UL1 TR000371 NCATS NIH HHS
• T32 CA101642 NCI NIH HHS
• CA128797 NCI NIH HHS

Cisplatin treatment has an overall 19% response rate in animal models with malignant tumors. Increasing gap junction activity in tumor cells provides the targets to enhance antineoplastic therapies. Previously, a new class of substituted quinolines (PQs) acts as gap junction enhancer, ability to increase the gap junctional intercellular communication, in breast cancer cells. We examined the effect of combinational treatment of PQs and antineoplastic drugs in an animal model, showing an increase in efficacy of antineoplastic drugs via the enhancement of gap junctions. Mice were implanted with estradiol-17ß (1.7 mg/pellet) before the injection of 1×10⁷ T47D breast cancer cells subcutaneously into the inguinal region of mammary fat pad. Animals were treated intraperitoneally with DMSO (control), cisplatin (3.5 mg/kg), PQ (25 mg/kg), or a combining treatment of cisplatin and PQ. Cisplatin alone decreased mammary tumor growth by 85% while combinational treatment of cisplatin and PQ1 or PQ7 showed an additional reduction of 77% and 22% of tumor growth after 7 treatments at every 2 days, respectively. Histological results showed a significant increase of gap junction proteins, Cx43 and Cx26, in PQ-treated tissues compared to control or cisplatin. Furthermore, evidence of highly stained caspase 3 in tumors of combinational treatment (PQ and cisplatin) was seen compared to cisplatin alone. We have showed for the first time an increase in the efficacy of antineoplastic drugs through a combinational treatment with PQs, a specific class of gap junction enhancers.

• Animals
• Antineoplastic Agents/pharmacology
• Cell Line, Tumor
• Cell Proliferation/drug effects
• Cisplatin/pharmacology
• Connexin 26
• Connexins
• Gap Junctions/drug effects
• Gap Junctions/metabolism
• Humans
• Mammary Neoplasms, Experimental/metabolism
• Mammary Neoplasms, Experimental/pathology
• Mice
• Mice, Nude
• Xenograft Model Antitumor Assays

• P30 RR030926 NCRR NIH HHS
• R15 CA152922 NCI NIH HHS
• P30RR030926 NCRR NIH HHS
• 1R15CA152922 NCI NIH HHS

As a prelude to combination studies aimed at resistance reversal, this dose-escalation/dose-expansion study investigated the selective Src kinase inhibitor saracatinib (AZD0530) in combination with carboplatin and/or paclitaxel.

Patients with advanced solid tumours received saracatinib once-daily oral tablets in combination with either carboplatin AUC 5 every 3 weeks (q3w), paclitaxel 175 mg m⁻² q3w, paclitaxel 80 mg m⁻² every 1 week (q1w), or carboplatin AUC 5 plus paclitaxel 175 mg m⁻² q3w. The primary endpoint was safety/tolerability.

A total of 116 patients received saracatinib 125 (N=20), 175 (N=44), 225 (N=40), 250 (N=9), or 300 mg (N=3). There were no clear dose-related trends within each chemotherapy regimen group in number or severity of adverse events (AEs). However, combining all groups, the occurrence of grade ⩾3 asthenic AEs (all causality) was dose-related (125 mg, 10% 175 mg, 20% ⩾225 mg, 33%), and grade ⩾3 neutropenia occurred more commonly at doses ⩾225 mg. There was no evidence that saracatinib affected exposure to carboplatin or paclitaxel, or vice versa. Objective responses were seen in 5 out of 44 patients (11%) receiving carboplatin plus paclitaxel q3w, and 5 out of 24 (21%) receiving paclitaxel q1w.

Saracatinib doses up to 175 mg with paclitaxel with/without carboplatin showed acceptable toxicity in most patients, and are suitable for further trials.

• PQ1
• cisplatin
• connexin
• cytotoxicity
• gap junction

Genetic interactions are functional crosstalk among different genetic loci that lead to phenotypic changes, such as health or viability alterations. A disease or lethal phenotype that results from the combined effects of gene mutations at different loci is termed a synthetic sickness or synthetic lethality, respectively. Studies of genetic interaction have provided insight on the relationships among biochemical processes or pathways. Cancer results from genetic interactions and is a major focus of current studies in genetic interactions. Various basic and translational cancer studies have explored the concept of genetic interactions, including studies of the mechanistic characterization of genes, drug discovery, biomarker identification and the rational design of combination therapies. This review discusses the implications of genetic interactions in the development of personalized cancer therapies, the identification of treatment-responsive genes, the delineation of mechanisms of chemoresistance and the rational design of combined therapeutic strategies to overcome drug resistance.

• Cancer
• Drug discovery
• Mutation
• Genetic interaction
• Target identification
• Chemoresistance

• ovarian cancer
• mucinous
• oxaliplatin
• dasatinib
• src kinase

• Adenocarcinoma, Mucinous/drug therapy
• Adenocarcinoma, Mucinous/genetics
• Adenocarcinoma, Mucinous/pathology
• Adult
• Aged
• Animals
• Antineoplastic Agents/therapeutic use
• Apoptosis/drug effects
• Blotting, Western
• Cell Line, Tumor
• Cell Survival
• Dasatinib
• Female
• Gene Expression Regulation, Neoplastic
• Humans
• Kaplan-Meier Estimate
• Mice
• Mice, Nude
• Middle Aged
• Neoplasm Staging
• Oligonucleotide Array Sequence Analysis
• Organoplatinum Compounds/administration & dosage
• Organoplatinum Compounds/pharmacology
• Ovarian Neoplasms/drug therapy
• Ovarian Neoplasms/genetics
• Ovarian Neoplasms/pathology
• Oxaliplatin
• Protein Kinase Inhibitors/administration & dosage
• Protein Kinase Inhibitors/pharmacology
• Pyrimidines/administration & dosage
• Pyrimidines/pharmacology
• Thiazoles/administration & dosage
• Thiazoles/pharmacology
• Xenograft Model Antitumor Assays
• src-Family Kinases/antagonists & inhibitors
• src-Family Kinases/genetics
• src-Family Kinases/metabolism

• P30 CA016672 NCI NIH HHS
• CA16672 NCI NIH HHS
• P50 CA098258 NCI NIH HHS
• P50 CA083639 NCI NIH HHS
• R01 CA128797 NCI NIH HHS
• T32 CA101642 NCI NIH HHS
• CA128797 NCI NIH HHS
• R01 CA109298 NCI NIH HHS
• RC2GM092599 NIGMS NIH HHS
• R01 CA110793 NCI NIH HHS
• RC2 GM092599 NIGMS NIH HHS
• CA110793 NCI NIH HHS
• 109298 PHS HHS

Extracellular matrix factors within the tumor microenvironment that control resistance to chemotherapeutics are poorly understood. This study focused on understanding matrix adhesion pathways that control the oral carcinoma response to cisplatin. Our studies revealed that adhesion of HN12 and JHU012 oral carcinomas to carcinoma matrix supported tumor cell proliferation in response to treatment with cisplatin. Proliferation in response to 30 µM cisplatin was not observed in HN12 cells adherent to other purified extracellular matrices such as Matrigel, collagen I, fibronectin or laminin I. Integrin β₁ was important for adhesion to carcinoma matrix to trigger proliferation after treatment with cisplatin. Disruption of talin expression in HN12 cells adherent to carcinoma matrix increased cisplatin induced proliferation. Pharmacological inhibitors were used to determine signaling events required for talin deficiency to regulate cisplatin induced proliferation. Pharmacological inhibition of NF-kB reduced proliferation of talin-deficient HN12 cells treated with 30 µM cisplatin. Nuclear NF-kB activity was assayed in HN12 cells using a luciferase reporter of NF-kB transcriptional activity. Nuclear NF-kB activity was similar in HN12 cells adherent to carcinoma matrix and collagen I when treated with vehicle DMSO. Following treatment with 30 µM cisplatin, NF-kB activity is maintained in cells adherent to carcinoma matrix whereas NF-kB activity is reduced in collagen I adherent cells. Expression of talin was sufficient to trigger proliferation of HN12 cells adherent to collagen I following treatment with 1 and 30 µM cisplatin. Talin overexpression was sufficient to trigger NF-kB activity following treatment with cisplatin in carcinoma matrix adherent HN12 cells in a process disrupted by FAK siRNA. Thus, adhesions within the carcinoma matrix create a matrix environment in which exposure to cisplatin induces proliferation through the function of integrin β₁, talin and FAK pathways that regulate NF-kB nuclear activity.

• Cell Line, Tumor
• Cell Nucleus/drug effects
• Cell Nucleus/metabolism
• Cell Proliferation/drug effects
• Cell-Matrix Junctions/drug effects
• Cell-Matrix Junctions/metabolism
• Cisplatin/pharmacology
• Crk-Associated Substrate Protein/metabolism
• Drug Resistance, Neoplasm/drug effects
• Extracellular Matrix/drug effects
• Extracellular Matrix/metabolism
• Humans
• Integrin beta1/metabolism
• Intracellular Space/drug effects
• Intracellular Space/metabolism
• Models, Biological
• Mouth Neoplasms/metabolism
• Mouth Neoplasms/pathology
• NF-kappa B/metabolism
• Signal Transduction/drug effects
• Talin/metabolism

• K08 CA132988 NCI NIH HHS
• Howard Hughes Medical Institute
• 1K08CA132988-01A2 NCI NIH HHS

• Antineoplastic Agents/pharmacology
• Biological Transport, Active
• Blotting, Western
• Cell Communication/drug effects
• Cell Survival/drug effects
• Cisplatin/pharmacology
• Coloring Agents
• Connexins/antagonists & inhibitors
• Connexins/biosynthesis
• Dose-Response Relationship, Drug
• Gap Junctions/drug effects
• HeLa Cells
• Humans
• Liposomes/chemistry
• Organoplatinum Compounds/pharmacology
• Oxaliplatin

• bosutinib
• dasatinib
• egfr
• saracatinib
• src inhibitors
• vegf

• Antineoplastic Agents/pharmacology
• Antineoplastic Agents/therapeutic use
• Biomarkers, Tumor
• Colorectal Neoplasms/drug therapy
• Disease Progression
• Drug Therapy, Combination
• ErbB Receptors/antagonists & inhibitors
• ErbB Receptors/drug effects
• Humans
• Oxidative Stress
• Signal Transduction/drug effects
• src-Family Kinases/antagonists & inhibitors
• src-Family Kinases/drug effects
• src-Family Kinases/metabolism

• K23 CA136980 NCI NIH HHS
• T32 CA009666 NCI NIH HHS
• CA136980 NCI NIH HHS