Cited by 328Computational Drug Discovery MethodsStatistical Methods in Clinical TrialsOptimal Experimental Design Methods

The DOI matches its Crossref record; 14 of the 14 references it cites were found in a registry or an index.

A New Bliss Independence Model to Analyze Drug Combination Data

Open access

Zhao, Wei, Sachsenmeier, Kris, Zhang, Lanju, Sult, Erin, Hollingsworth, Robert E., Yang, Harry·2014·SLAS Discovery

DOI 10.1177/1087057114521867

Open this paper in CoChat — free account Open PDF

Abstract

The Bliss independence model is widely used to analyze drug combination data when screening for candidate drug combinations. The method compares the observed combination response (Y(O)) with the predicted combination response (Y(P)), which was obtained based on the assumption that there is no effect from drug-drug interactions. Typically, the combination effect is declared synergistic if Y(O) is greater than Y(P). However, this method lacks statistical rigor because it does not take into account the variability of the response measures and can frequently cause false-positive claims. In this article, we introduce a two-stage response surface model to describe the drug interaction across all dose combinations tested. This new method enables robust statistical testing for synergism at any dose combination, thus reducing the risk of false positives. The use of the method is illustrated through an application describing statistically significant "synergy regions" for candidate drug combinations targeting epidermal growth factor receptor and the insulin-like growth factor 1 receptor.

Integrity signals

Registry

Crossref · 10.1177/1087057114521867

Cites

14 of 14 references verified0 citation errors · 0 not checkable

Statistics

Recomputing p-values needs the paper’s full text.

Claims the paper makes

We couldn’t retrieve this paper’s full text, so its claims and self-check weren’t run. The registry and citation checks still apply.

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

The search for synergy: a critical review from a response surface perspective.
Greco, W. R., Bravo, G., & Parsons, J. C. (1995) · Pharmacological Reviews · doi:10.1016/s0031-6997(25)06847-4 · Cited by 1,445
Probability Theory and Mathematical Statistics
(1996) · doi:10.1142/2898 · Cited by 1,406
Activation of Multiple Proto-oncogenic Tyrosine Kinases in Breast Cancer via Loss of the PTPN12 Phosphatase
Sun, T., Aceto, N., Meerbrey, K. L., Kessler, J. D., Zhou, C., Migliaccio, I., Nguyen, D. X., Pavlova, N. N., Botero, M. F., Huang, J., et al. (2011) · Cell · doi:10.1016/j.cell.2011.02.003 · Cited by 281 · cited 4×
“I Y Y M a b ab O ab P = − = + , , ( | , ) Γ ε, (3)”
BackgroundMethodInfluential
A global analysis of cross-talk in a mammalian cellular signalling network
Natarajan, M., Lin, K.-M., Hsueh, R. C., Sternweis, P. C., & Ranganathan, R. (2006) · Nature Cell Biology · doi:10.1038/ncb1418 · Cited by 235 · cited 1×
“Average percentage inhibition is usually used when replicates are available and a conclusion can be drawn by strictly following equations (1) and (2).”
Method
Probability Theory and Mathematical Statistics.
Bartholomew, D. J., & Fisz, M. (1964) · Biometrika · doi:10.2307/2334227 · Cited by 161
A stable IgG-like bispecific antibody targeting the epidermal growth factor receptor and the type I insulin-like growth factor receptor demonstrates superior anti-tumor activity
Dong, J., Sereno, A., Aivazian, D., Langley, E. J., Miller, B., Snyder, W. B., Chan, E., Cantele, M., Morena, R., Joseph, I. B. J., et al. (2011) · mAbs · doi:10.4161/mabs.3.3.15188 · Cited by 80
Activation of the Insulin-like Growth Factor-1 Receptor Induces Resistance to Epidermal Growth Factor Receptor Antagonism in Head and Neck Squamous Carcinoma Cells
Jameson, M. J., Beckler, A. D., Taniguchi, L. E., Allak, A., VanWagner, L. B., Lee, N. G., Thomsen, W. C., Hubbard, M. A., & Thomas, C. Y. (2011) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-11-0294 · Cited by 79
The EGF receptor interacts with the type 1 IGF receptor and regulates its stability
Riedemann, J., Takiguchi, M., Sohail, M., & Macaulay, V. M. (2007) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2007.02.012 · Cited by 77
Dual inhibition of epidermal growth factor receptor and insulin‐like growth factor receptor I: Reduction of angiogenesis and tumor growth in cutaneous squamous cell carcinoma
Galer, C. E., Corey, C. L., Wang, Z., Younes, M. N., Gomez‐Rivera, F., Jasser, S. A., Ludwig, D. L., El‐Naggar, A. K., Weber, R. S., & Myers, J. N. (2010) · Head & Neck · doi:10.1002/hed.21419 · Cited by 53
Rational Design of Cancer-Drug Combinations
Ramaswamy, S. (2007) · New England Journal of Medicine · doi:10.1056/nejmcibr072593 · Cited by 48 · cited 1×
“Average percentage inhibition is usually used when replicates are available and a conclusion can be drawn by strictly following equations (1) and (2).”
Method

Show all 14 references

Sorted by citations

Items 201–300 of 328

mTOR Inhibition Enhances Delivery and Activity of Antisense Oligonucleotides in Uveal Melanoma Cells
Dewaele, S., Delhaye, L., Paepe, B. D., Bogaert, B., Martinez, R., Anckaert, J., Yigit, N., Nuytens, J., Coster, R. V., Eyckerman, S., et al. (2023) · Nucleic Acid Therapeutics · doi:10.1089/nat.2023.0008 · Cited by 3
“We observed synergistic effects, calculated by means of excess over Bliss scores [36], for 6 compound— SAMMSON ASO combinations (ie, amsacrine, GDC-0349, mifepristone, CI-994, entinostat, and INH-6) (Fig.”
XBP1 promotes NRASG12D pre‐B acute lymphoblastic leukaemia through IL ‐7 receptor signalling and provides a therapeutic vulnerability for oncogenic RAS
Salimi, A., Schemionek, M., Huber, M., Vieri, M., Patterson, J. B., Alten, J., Brümmendorf, T. H., Masouleh, B. K., & Appelmann, I. (2023) · Journal of Cellular and Molecular Medicine · doi:10.1111/jcmm.17904 · Cited by 3
SHP2 Inhibition Abrogates MEK inhibitor Resistance in Multiple Cancer ModelsPreprint
Fedele, C., Ran, H., Diskin, B., Wei, W., Jen, J., Araki, K. Y., Simeone, D. M., Miller, G., Neel, B. G., & Tang, K. H. (2018) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/307876 · Cited by 3
Anticancer and apoptotic effects of orange peel extract and naringin on doxorubicin-induced apoptosis in human esophageal squamous carcinoma cell linePreprint
Tajodini, M., Samadi, F., Asadi, J., Khosravi, A., & Samadi, F. (2023) · Research Square · doi:10.21203/rs.3.rs-3068410/v1 · Cited by 3
Resolving discrepancies between chimeric and multiplicative measures of higher-order epistasis
Chitra, U., Arnold, B., & Raphael, B. J. (2025) · Nature Communications · doi:10.1038/s41467-025-56986-5 · Cited by 2
Polatuzumab Vedotin Induced CD20 Upregulation Contributes to the Efficacy of Mosunetuzumab in Combination With Polatuzumab Vedotin in Diffuse Large B‐Cell Lymphoma Preclinical Models
Kawasaki, N., Shu, S., Tomita, M., Liu, X., Yoshiura, S., & Yamashita‐Kashima, Y. (2025) · eJHaem · doi:10.1002/jha2.70169 · Cited by 2
“The evaluation of the synergistic combination effect was conducted using the Bliss independence model [19, 20].”
Synergistic Genotoxic Effects of Gamma Rays and UVB Radiation on Human Blood
Gkikoudi, A., Adamopoulou, A., Diamadaki, D., Matsades, P., Tzakakos, I., Triantopoulou, S., Vasilopoulos, S. N., Manda, G., Terzoudi, G. I., & Georgakilas, A. G. (2025) · Antioxidants · doi:10.3390/antiox14121451 · Cited by 2
“Typically, the combination effect is declared synergistic if E AB _ obs is higher than E AB _ exp [13].”
Quantitative ex vivo assessment of chemotherapy synergy using patient-derived non-Hodgkin lymphoma samples
Kim, J. W., Ko, N., Ham, S., Courcoubetis, G., Han, M. W., Ahn, Y., Yi, H., Lim, S., Lee, J. C., & Koo, J. (2026) · Biotechnology and Bioprocess Engineering · doi:10.1007/s12257-025-00249-z · Cited by 2
“The Bliss model calculates the expected combination effect based on the multiplicative probabilities of independent drug actions; a positive Bliss score indicates synergy, zero indi - cates additivity, and a negative score indicates antagonism [13].”
Resveratrol as a Novel YAP Inhibitor Targeting Glioblastoma Progression and Sensitizing to Chemotherapy
Khotchawan, W., Lorthongpanich, C., Kheolamai, P., Sathornsumetee, S., & Issaragrisil, S. (2026) · Cancer Science · doi:10.1111/cas.70317 · Cited by 2
“In addition, analysis of the data presented in Figure 8 using the Highest Single Agent (HSA) model demonstrated positive effects across all cell lines, whereas the Bliss Independence model revealed synergistic interactions in all combinations of most cell lines (Table S2) [38–42].”
A Combination of Xanthohumol and Ursolic Acid in the Diet Leads to Synergistic Inhibition of Prostate Cancer Progression
Clark, R., Saha, A., Hackman, G. L., Friedman, C. A., Gorgoglione, R., Tiziani, S., & DiGiovanni, J. (2026) · Molecular Carcinogenesis · doi:10.1002/mc.70087 · Cited by 2
“Synergy was determined by Bliss index according to the formula C = A + B – AB, where A and B are the individual affected fractions and C is the theoretical affected fraction of the combination [28].”
Auranofin and iodoquinol as promising repurposing drugs against filamentous fungi: antifungal activity and cellular alterations
Xisto, M. I. D. D. S., Rollin‐Pinheiro, R., da Rosa, P. C. M., Santos, J. D. S., Irmão, N. F. D. S., Abib, J. A. A., Rochetti, V. P., de Castro-Almeida, Y., Freitas, G. M. P. D. S., Cypriano, J. B. S., et al. (2026) · Microbiology Spectrum · doi:10.1128/spectrum.03356-25 · Cited by 2
“The Bliss independence model calculation was performed according to Meletiadis and colleagues and Zhao and colleagues (26, 27).”
Sulforaphane Synergies with Phytochemicals and Pharmaceuticals: Implications for Healthspan
Fahey, J. W., & Liu, H. (2026) · Medicines · doi:10.3390/medicines13020016 · Cited by 2
“Report comprehensive dose–response matrices and employ the Chou–Talalay [10] or Bliss independence [235] methods.”
SİNERJİSTİK İLAÇ KOMBİNASYONLARININ ANALİZİNDE GÜNCEL MATEMATİKSEL VE İSTATİSTİKSEL YÖNTEMLER
ÖZER, B. O. (2023) · Ankara Universitesi Eczacilik Fakultesi Dergisi · doi:10.33483/jfpau.1180259 · Cited by 3
Fusing Micro- and Macro-Scale Information to Predict Anticancer Synergistic Drug Combinations
Wang, X., Zhu, H., Liu, Q., & Liu, Q. (2024) · IEEE Journal of Biomedical and Health Informatics · doi:10.1109/jbhi.2024.3500789 · Cited by 2
“We selected the Loewe synergy score as regression objective as the BLISS model are more likely to provide false positive results [50].”
Combining the P2Y12 antagonist cangrelor with energy metabolism inhibitors has a synergistic antiaggregatory effect
Kurpińska, A., Lytvynenko, O., Kij, A., Przyborowski, K., Berkowicz, P., Rafa–Zabłocka, K., Chłopicki, S., & Kaczara, P. (2025) · Biochemical Pharmacology · doi:10.1016/j.bcp.2025.117056 · Cited by 2
Combination of NDRG2 overexpression, X-ray radiation and docetaxel enhances apoptosis and inhibits invasiveness properties of LNCaP cells
Zarei, M. A., Dehbidi, G. R., & Takhshid, M. A. (2020) · Urologic Oncology Seminars and Original Investigations · doi:10.1016/j.urolonc.2020.06.017 · Cited by 2
A same‐day assay predicts apoptotic response to combined BCL‐2 and MCL‐1 BH3‐mimetic targeting in multiple myeloma cells
Grundy, M. A., Al‐Kaisi, F., Cull, J., Williams, C. D., Smith, D., & Seedhouse, C. (2020) · eJHaem · doi:10.1002/jha2.133 · Cited by 1
“Foldexcess additivismwascalculatedasa ratioofobserved toexpected values for drug combinations, where the expected value C is calculated from the Bliss algorithm for response to two compoundswith effects A and B that is C=A+ B−A × B [14].”
Method
Enhanced Sestrin expression through Tanshinone 2A treatment improves PI3K-dependent inhibition of glioma growthPreprint
Williams, R. S. B., Schaf, J., Shinhmar, S., Zeng, Q., Pardo, O. E., Beesley, P. W., & Syed, N. (2022) · Research Square · doi:10.21203/rs.3.rs-2178722/v1 · Cited by 2
Reduced mitochondrial transcription sensitizes acute myeloid leukemia cells to BCL-2 inhibitionPreprint
Arabanian, L. S., Adamsson, J., Unger, A., Lucrezia, R. D., Bergbrede, T., Ashouri, A., Larsson, E., Nußbaumer, P., Klebl, B., Palmqvist, L., et al. (2024) · eLife · doi:10.7554/elife.97749.1 · Cited by 2
Dual Targeting of CX3CR1 and PARP in Models of High-Grade Serous Ovarian Carcinoma
Xie, J., & Barbolina, M. V. (2024) · Cancers · doi:10.3390/cancers16223728 · Cited by 1
Synergistic Effects of 2-Deoxyglucose and Diclofenac Sodium on Breast Cancer Cells: A Comparative Evaluation of MDA-231 and MCF7 Cells
Maloba, G. O., Were, T., Barasa, E., Mohamed, N., Arshi, A., & Gallyas, F. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26104894 · Cited by 1
Early ageing in Caenorhabditis elegans caused by exposure to airborne benzene, toluene, ethylbenzene and xylenes (BTEX)
Soares, M. V., Cordeiro, L. M., da Silva, A. F., Ugalde, G. A., Venturini, L., Soares, F. A. A., & Ávila, D. S. (2025) · Chemosphere · doi:10.1016/j.chemosphere.2025.144624 · Cited by 1
Synergistic inhibition of CHK1 and MUS81 to combat replication stress resistance in high-risk neuroblastoma
Hilgert, E., Neste, C. V., Bekaert, S.-L., Martens, F., Vanhauwaert, S., Sanders, E., Verstraelen, P., Risseeuw, M., Westerhout, E. M., Grannetia, M. A., et al. (2025) · Scientific Reports · doi:10.1038/s41598-025-29898-z · Cited by 1
“The HTSplotter tool was used to perform BR analysis and evaluate synergism using the Bliss Independent (BI) method 63,64 .”
Hesperetin’s antigenotoxicity: the impact on EMS-made lesions within Drosophila melanogaster somatic cells’ DNA, disclosed through molecular modeling
Matić, S. L., Stanković, N., Božović, M., Astolfi, R., Giuliani, L., Ragno, R., & Mladenović, M. P. (2025) · Phytomedicine · doi:10.1016/j.phymed.2025.157728 · Cited by 1
Phytocannabinoids as anti-inflammatory agents: Synergistic effects when combined with Cannabis sativa L. matrices
Strnad, O., Nejedlý, T., Svoboda, P., Mertlíková‐Kaiserová, H., Malý, M., Malý, M., Stranska-Zachariasova, M., & Viktorová, J. (2025) · Journal of Ethnopharmacology · doi:10.1016/j.jep.2025.121134 · Cited by 1
Panduratin A from Boesenbergia rotunda suppresses hepatitis B virus by targeting HNF1α and synergizing with antiviral agents
Thongsri, P., Pewkliang, Y., Borwornpinyo, S., Wongkajornsilp, A., Ruenraroengsak, P., Anurathapan, U., Sobhonslidsuk, A., Hongeng, S., & Sa‐ngiamsuntorn, K. (2026) · Chinese Medicine · doi:10.1186/s13020-025-01285-w · Cited by 2
“The combination of panduratin A and GS-5801 significantly inhibited HBV replication, confirmed by Bliss model analysis [62].”
Fisetin-loaded Nanoemulsion and Fecal Microbiome Extract Enhance In Vitro Inhibition of Non-Small Cell Lung Cancer Progression
Haysom‐McDowell, A., Paudel, K. R., Mehndiratta, S., Singh, M., Malik, M. Z., Kokkinis, S., Pakan, P. D., Williams, F. E., Singh, S. K., Dua, K., et al. (2026) · Cell Biochemistry and Biophysics · doi:10.1007/s12013-025-01981-2 · Cited by 1
“Additionally, while various microorganism strains have been identified in the current FME, the microbiome is a highly complex ecosystem with in excess of 2000 species, is warranted [76, 77].”
Therapeutic potential of BH3-mimetics and NK cell-mediated immunotherapy in T-ALL
Fortner, C., Niedermayer, A., Bäuerle, M. M., Wichert, M. C., Braun, C. J., Debatin, K., Vogler, M., Meyer, L. H., & Seyfried, F. (2026) · Cell Death and Disease · doi:10.1038/s41419-026-08698-x · Cited by 1
Treatment of periodontal biofilms via nitric oxide-augmented phototherapy
Johnson, C. R., Ramrattan, T. D., Schaefer, C. J., Kumar, R. U., Reinhard, S. J., Wallet, S. M., & Schoenfisch, M. H. (2026) · Journal of Oral Microbiology · doi:10.1080/20002297.2026.2658899 · Cited by 1
“To determine the synergistic, antagonistic or independent behaviour of the treatment, the predicted treatment efficiency (Y LED/NO,P ) was calculated according to the Bliss independence model [43] (Equation 3), where Y LED is the LED treatment and Y NO is the NO-releasing material.”
EBNA1 inhibitors reveal CDC7 and POU2F1 as direct functional targets in EBV epithelial cancers
He, S., Terhuja, N., Soldan, S. S., Chen, C., Cassel, J., Yin, X., Liu, Q., Chung, S. S., Castro-Muñoz, L. J., Yoon, L., et al. (2026) · mBio · doi:10.1128/mbio.00329-26 · Cited by 1
“The SynergyFinder package (3.0) in the R program was utilized to analyze synergistic effects between two inhibitors using a two-stage response surface model (92).”
Influential
Standardizing antiviral response metrics for mono- and combination therapies in acute, chronic and latent viral infections
Petakh, P., Ravlo, E., Pan, Q., Bruzzone, R., Oksenych, V., Vähä-Koskela, M. J. V., Kamyshnyi, O., & Kainov, D. E. (2026) · Virology Journal · doi:10.1186/s12985-026-03202-5 · Cited by 1
“Some reports relied on single-concentration inhibition values, others reported EC₅₀ values without matched toxicity measurements, and relatively few applied formal synergy or resistance metrics [7, 8].”
High-throughput pesticide toxicity assessment in Black Soldier Fly (Hermetia illucens) by behavioral phenomics
Siregar, P., Audira, G., Kurnia, K. A., Wang, S., Roldan, M. J. M., Bonalos, K. M., Vasquez, R. D., Lin, M., & Hsiao, C. (2026) · Pesticide Biochemistry and Physiology · doi:10.1016/j.pestbp.2026.107244 · Cited by 2
Screening of organophosphorus pesticide-degrading bacteria and a ratio-optimized consortium for efficient phoxim and malathion removal with pathway inference
Tang, X., Waheed, M., Xu, Q., Liu, X., Xie, R., Geng, A., & Zhu, D. (2026) · International Biodeterioration & Biodegradation · doi:10.1016/j.ibiod.2026.106419 · Cited by 1
Drug Combination Synergy
Yang, H. C., Novick, S. J., & Zhao, W. (2014) · Chapman & Hall/CRC eBooks · doi:10.1201/b17965-5 · Cited by 1
Self-citation
Hit Discovery Methodology
Wigglesworth, M. J., & Hodder, P. (2021) · SLAS DISCOVERY · doi:10.1177/2472555220982257 · Cited by 1
Cell membrane permeability and defective G2/M block as factors potentially contributing to increased cell chemosensitivity. SeAx cell line as an example
Biskup, E., Niazi, O., & Pless, V. (2021) · Biochemistry and Biophysics Reports · doi:10.1016/j.bbrep.2021.101005 · Cited by 1
“In this model YAB,O > YAB,P means synergy, while YAB,O = YAB,P means additive effect [11].”
BackgroundMethod
Bioinformatic strategies to understand the complexities of medicinal natural product mixtures
Caesar, L. K. (2019) · NC Digital Online Collection of Knowledge and Scholarship (The University of North Carolina at Greensboro) · Cited by 1
Enzymatic depletion of l ‐Met using an engineered human enzyme as a novel therapeutic strategy for melanoma
Wilder, C. S., Chiou, J., Battenhouse, A. M., Saha, A., Chen, Z., Kim, E., Gadallah, M. I., Tiziani, S., Georgiou, G., Stone, E. M., et al. (2023) · Molecular Carcinogenesis · doi:10.1002/mc.23597 · Cited by 1
“The synergy of drug combinations was assessed with the widely utilized Bliss Independence model.(24) Statistical methods were used to predetermine the sample size for animal experiments.”
Method
Research Techniques Made Simple: Preclinical Development of Combination Antitumor Targeted Therapies in Dermatology
Yumeen, S., Mirza, F. N., Lewis, J. M., & Girardi, M. (2020) · Journal of Investigative Dermatology · doi:10.1016/j.jid.2020.09.020 · Cited by 1
Fenretinide targets GATA1 to induce cytotoxicity in GATA1 positive Acute Erythroid and Acute Megakaryoblastic Leukemic cellsPreprint
Raza, Y., Elmasry, M., Yu, G., Chiappone, S. B., Liu, S., & Luberto, C. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.01.19.633759 · Cited by 1
Design and Evaluation of Drug Combination Studies
Zhang, L., & Yang, H. (2016) · Statistics for biology and health · doi:10.1007/978-3-319-23558-5_13
Self-citation
Novel Hormonal Combination Therapy for Triple Negative Breast Cancer
Thakkar, A. (2016)
Physiology Directed Drug Discovery in Multidrug Resistant Plasmodium falciparum
Siriwardana, A. (2017) · DigitalGeorgetown (Georgetown University Library)
ABiparatopicHER2-TargetingAntibody-DrugConjugate Induces Tumor Regression in Primary Models RefractorytoorIneligibleforHER2-TargetedTherapy
Li, J. Y., Perry, S. R., Muniz-Medina, V. M., Wang, X., Wetzel, L. K., Rebelatto, M. C., Jane, M., Hinrichs, M., Bezabeh, B. Z., Fleming, R. L., et al. (2016)
Evaluation of the mevalonate pathway as a target for the treatment of ovarian cancer
Abdullah, M. I. (2018) · Keele Research Repository (Keele University)
Cell-based models for studying paediatric high-grade gliomas
Larsson, S. C. (2019) · Gothenburg University Publications Electronic Archive (Gothenburg University)
Interactive Effects of Salinity and Cadmium Pollution on Enzyme Activity in a Calcareous Soil Treated With Plant Residues
Sadeghi, E., Raiesi, F., & Hossienpur, A. R. (2019) · JWSS - Isfahan University of Technology · doi:10.29252/jstnar.23.2.361
Dinaciclib Inhibits Glioblastoma Multiforme Cell Growth and Selects for a Brain Tumour Initiating Cell Population
Stover, M. (2019) · Scholarship at UWindsor (University of Windsor)
Covid-19 meets game theory: a proposed experimentPreprint
Stamatopoulos, G. (2021) · Research Square · doi:10.21203/rs.3.rs-829620/v1
The effects of NX-AS-401 on methicillin resistant Staphylococcus aureus
Butterick, P. (2021) · Cronfa (Swansea University) · doi:10.23889/suthesis.59037
COVID-19 Meets Game Theory: A Proposed ExperimentPreprint
Stamatopoulos, G. (2021) · SSRN Electronic Journal · doi:10.2139/ssrn.3910937
“As a reference case, we ﬁrst present the Bliss independence model for the two-drug case (Zhao et al. 2014; Demidenko and Miller 2019).”
Reduced mitochondrial transcription sensitizes acute myeloid leukemia cells to BCL-2 inhibitionPreprint
Arabanian, L. S., Adamsson, J., Unger, A., Lucrezia, R. D., Bergbrede, T., Ashouri, A., Larsson, E., Nußbaumer, P., Klebl, B., Palmqvist, L., et al. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.09.23.509145
“7 express wild type TP53, as determined by combination analysis (Bliss-independence model 124 (16)).”
Supplementary Data from A Combinatorial CRISPR–Cas9 Screen Identifies Ifenprodil as an Adjunct to Sorafenib for Liver Cancer Treatment
Xu, F., Tong, M., Tong, C. S. W., Chan, B. K. C., Chu, H. Y., Wong, T. L., Fong, J. H. C., Cheung, M. S. H., Mak, K. H.-M., Pardeshi, L. A., et al. (2023) · doi:10.1158/0008-5472.22430385
Supplementary Data from A Combinatorial CRISPR–Cas9 Screen Identifies Ifenprodil as an Adjunct to Sorafenib for Liver Cancer Treatment
Xu, F., Tong, M., Tong, C. S. W., Chan, B. K. C., Chu, H. Y., Wong, T. L., Fong, J. H. C., Cheung, M. S. H., Mak, K. H.-M., Pardeshi, L. A., et al. (2023) · doi:10.1158/0008-5472.22430385.v1
Supplementary Data from Antitumor Synergism and Enhanced Survival with a Tumor Vasculature–Targeted Enzyme Prodrug System, Rapamycin, and Cyclophosphamide
Krais, J. J., Virani, N. A., McKernan, P., Nguyen, Q., Fung, K.-M. A., Sikavitsas, V. I., Kurkjian, C. D., & Harrison, R. G. (2023) · doi:10.1158/1535-7163.22507750.v1
Supplementary Figure 2 from Venetoclax-based Rational Combinations are Effective in Models of MYCN-amplified Neuroblastoma
Dalton, K. M., Krytska, K., Lochmann, T. L., Sano, R., Casey, C., D'Aulerio, A., Khan, Q. A., Crowther, G. S., Coon, C. M., Cai, J., et al. (2023) · doi:10.1158/1535-7163.22522659.v1
Data from Venetoclax-based Rational Combinations are Effective in Models of MYCN-amplified Neuroblastoma
Dalton, K. M., Krytska, K., Lochmann, T. L., Sano, R., Casey, C., D'Aulerio, A., Khan, Q. A., Crowther, G. S., Coon, C. M., Cai, J., et al. (2023) · doi:10.1158/1535-7163.c.6543453.v1
Data from Targeting BET Proteins BRD2 and BRD3 in Combination with PI3K-AKT Inhibition as a Therapeutic Strategy for Ovarian Clear Cell Carcinoma
Shigeta, S., Lui, G. Y. L., Shaw, R. C., Moser, R. D., Gurley, K. E., Durenberger, G., Rosati, R., Diaz, R. L., Ince, T. A., Swisher, E. M., et al. (2023) · doi:10.1158/1535-7163.c.6543286.v1
Data from Targeting BET Proteins BRD2 and BRD3 in Combination with PI3K-AKT Inhibition as a Therapeutic Strategy for Ovarian Clear Cell Carcinoma
Shigeta, S., Lui, G. Y. L., Shaw, R. C., Moser, R. D., Gurley, K. E., Durenberger, G., Rosati, R., Diaz, R. L., Ince, T. A., Swisher, E. M., et al. (2023) · doi:10.1158/1535-7163.c.6543286
Supplementary Data from Antitumor Synergism and Enhanced Survival with a Tumor Vasculature–Targeted Enzyme Prodrug System, Rapamycin, and Cyclophosphamide
Krais, J. J., Virani, N. A., McKernan, P., Nguyen, Q., Fung, K.-M. A., Sikavitsas, V. I., Kurkjian, C. D., & Harrison, R. G. (2023) · doi:10.1158/1535-7163.22507750
SynDISCO: A Mechanistic Modeling-Based Framework for Predictive Prioritization of Synergistic Drug Combinations Directed at Cell Signaling NetworksPreprint
Shin, S., & Nguyen, L. K. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.04.07.536087
“These include the Coefficient of Drug Interaction (CDI) model (28, 29), the Bliss Independence (BI) model (30, 31), the Chou-Talalay model (32), highest single agent (HSA) model (33) and zero interaction potency (ZIP) model (34, 35).”
BackgroundMethodInfluential
Νanomaterial-Loaded Polymer Coating Prevents the In Vitro Growth of Candida albicans Biofilms on Silicone Biomaterials
Tsikopoulos, A., Tsikopoulos, K., Meroni, G., Gravalidis, C., Soukouroglou, P., Chatzimoschou, A., Drago, L., Triaridis, S., & Papaioannidou, P. (2023) · Antibiotics · doi:10.3390/antibiotics12071103
“Synergy Assessment between Al2O3 and TiO2 The synergistic or antagonistic effects between Al2O3 and TiO2 were assessed in line with Bliss’s independence model [26].”
Method
Computational precision therapeutics and drug repositioning
Powell, R. T. (2023) · Elsevier eBooks · doi:10.1016/b978-0-12-824010-6.00063-0
Development of Antimicrobial Impregnated Catheter Coatings to Prevent Uropathogenic Escherichia coli Infections
Capper-Parkin, K. (2023) · Sheffield Hallam University · doi:10.7190/shu-thesis-00589
Additional file 7 of S6K1 amplification confers innate resistance to CDK4/6 inhibitors through activating c-Myc pathway in patients with estrogen receptor-positive breast cancer
Mo, H., Liu, X., Yu, X. F., Chen, H., Guo, S., Li, Z., Wang, S., Li, C., Han, J., Fu, M., et al. (2022) · Figshare · doi:10.6084/m9.figshare.20745219
Additional file 6 of S6K1 amplification confers innate resistance to CDK4/6 inhibitors through activating c-Myc pathway in patients with estrogen receptor-positive breast cancer
Mo, H., Liu, X., Yu, X. F., Chen, H., Guo, S., Li, Z., Wang, S., Li, C., Han, J., Fu, M., et al. (2022) · Figshare · doi:10.6084/m9.figshare.20745216
Additional file 4 of S6K1 amplification confers innate resistance to CDK4/6 inhibitors through activating c-Myc pathway in patients with estrogen receptor-positive breast cancer
Mo, H., Liu, X., Xue, Y., Chen, H., Guo, S., Li, Z., Wang, S., Li, C., Han, J., Fu, M., et al. (2022) · Figshare · doi:10.6084/m9.figshare.20745210
Additional file 5 of S6K1 amplification confers innate resistance to CDK4/6 inhibitors through activating c-Myc pathway in patients with estrogen receptor-positive breast cancer
Mo, H., Liu, X., Yu, X. F., Chen, H., Guo, S., Li, Z., Wang, S., Li, C., Han, J., Fu, M., et al. (2022) · Figshare · doi:10.6084/m9.figshare.20745213
Additional file 2 of S6K1 amplification confers innate resistance to CDK4/6 inhibitors through activating c-Myc pathway in patients with estrogen receptor-positive breast cancer
Mo, H., Liu, X., Yu, X. F., Chen, H., Guo, S., Li, Z., Wang, S., Li, C., Han, J., Fu, M., et al. (2022) · Figshare · doi:10.6084/m9.figshare.20745204
Reduced mitochondrial transcription sensitizes acute myeloid leukemia cells to BCL-2 inhibitionPreprint
Arabanian, L. S., Adamsson, J., Unger, A., Lucrezia, R. D., Bergbrede, T., Ashouri, A., Larsson, E., Nußbaumer, P., Klebl, B., Palmqvist, L., et al. (2024) · eLife · doi:10.7554/elife.97749
Quantifying higher-order epistasis: beware the chimeraPreprint
Chitra, U., Arnold, B., & Raphael, B. J. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.07.17.603976
“The chimeric measure has been widely used in the genetics literature (e.g. [23, 24, 25, 26, 27, 28, 29, 4, 30, 31, 32, 33, 34]) and in the drug interaction literature (e.g. [70, 71, 72, 73, 74, 75, 57, 43, 76, 77]).”
Method
Inhibition of Mesenchymal Phenotypes in Glioblastoma by Combined Targeting of NF-κB and STAT3 PathwaysPreprint
Ren, X., Li, J., Chen, L., Wang, X., Zhang, J., Zhang, Y., Fan, J., Yun, D., Zhang, C., Yu, S., et al. (2024) · Research Square · doi:10.21203/rs.3.rs-5305574/v1
Host-Directed Repurposed Diltiazem Enhances the Antiviral Activity of Classic Antivirals Against Influenza and Sars-Cov-2Preprint
Padey, B., Droillard, C., Dulière, V., Fouret, J., de Lamballerie, C. N., Milesi, C., Laurent, E., Brun, P., Traversier, A., Julien, T., et al. (2024) · SSRN Electronic Journal · doi:10.2139/ssrn.5041998
Combination Oxylanthanum Carbonate and Tenapanor Lowers Urinary Phosphate Excretion in Rats
Medicherla, S., Reddy, G., Gupta, P., Chertow, G. M., & Gupta, S. (2025) · Kidney360 · doi:10.34067/kid.0000000709
Connectivity mapping: Integrating omics data, drug targets, and disease drivers for drug discovery and repurposing
Siminea, N., Anand, P., Păun, A., Chiosis, G., Freeman, A., & Petre, I. (2025) · Elsevier eBooks · doi:10.1016/b978-0-443-29808-0.00021-2
Reduced mitochondrial transcription sensitizes acute myeloid leukemia cells to BCL-2 inhibitionPreprint
Arabanian, L. S., Adamsson, J., Unger, A., Lucrezia, R. D., Bergbrede, T., Ashouri, A., Larsson, E., Nußbaumer, P., Klebl, B., Palmqvist, L., et al. (2025) · eLife · doi:10.7554/elife.97749.2
Fubylation as a Druggable Ubiquitin-Like Conjugation System Controlling Hippo Pathway ActivityPreprint
Bulos, M. L., Grzelak, E. M., Nutsch, K., Elshan, N. G. R. D., Chatterjee, A. K., & Bollong, M. J. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.07.06.663376
“Interestingly, co-treatment of sCMF231 and PY-60, an ANXA2-inhibiting YAP activator previously identified by our group, synergistically activates TEAD-LUC reporter activity as determined by changes in Bliss independence calculations 36 (Fig.”
Enhancing the anticancer efficacy of a nitric oxide and formaldehyde co-donor through isotope substitution
Zhao, Z., Zhang, Y., Hou, C., Wan, J., Wang, P., Feng, X., & Luo, J. S. (2025) · Journal of Materials Chemistry B · doi:10.1039/d5tb02270c
Additional file 3 of S6K1 amplification confers innate resistance to CDK4/6 inhibitors through activating c-Myc pathway in patients with estrogen receptor-positive breast cancer
Mo, H., Liu, X., Xue, Y., Chen, H., Guo, S., Li, Z., Wang, S., Li, C., Han, J., Fu, M., et al. (2022) · Figshare · doi:10.6084/m9.figshare.20745207
Additional file 11 of S6K1 amplification confers innate resistance to CDK4/6 inhibitors through activating c-Myc pathway in patients with estrogen receptor-positive breast cancer
Mo, H., Liu, X., Xue, Y., Chen, H., Guo, S., Li, Z., Wang, S., Li, C., Han, J., Fu, M., et al. (2022) · Figshare · doi:10.6084/m9.figshare.20745189
Additional file 8 of S6K1 amplification confers innate resistance to CDK4/6 inhibitors through activating c-Myc pathway in patients with estrogen receptor-positive breast cancer
Mo, H., Liu, X., Xue, Y., Chen, H., Guo, S., Li, Z., Wang, S., Li, C., Han, J., Fu, M., et al. (2022) · Figshare · doi:10.6084/m9.figshare.20745222
Additional file 9 of S6K1 amplification confers innate resistance to CDK4/6 inhibitors through activating c-Myc pathway in patients with estrogen receptor-positive breast cancer
Mo, H., Liu, X., Xue, Y., Chen, H., Guo, S., Li, Z., Wang, S., Li, C., Han, J., Fu, M., et al. (2022) · Figshare · doi:10.6084/m9.figshare.20745225
Additional file 1 of The potential of PARP as a therapeutic target across pediatric solid malignancies
Keller, K. M., Koetsier, J., Schild, L. G., Amo-Addae, V., Eising, S., van den Handel, K., Ober, K., Koopmans, B., Essing, A. H. W., van den Boogaard, M. L., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26580593
Additional file 2 of Combined targeting of MEK and the glucocorticoid receptor for the treatment of RAS-mutant multiple myeloma
Sriskandarajah, P., de Haven‐Brandon, A., Macleod, K., Carragher, N. O., Kirkin, V., Kaiser, M., & Whittaker, S. R. (2020) · Figshare · doi:10.6084/m9.figshare.12050775
Additional file 2 of Combined inhibition of HMGCoA reductase and mitochondrial complex I induces tumor regression of BRAF inhibitor-resistant melanomas
de Groot, E., Varghese, S., Tan, L., Knighton, B. G., Sobieski, M. M., Nguyen, N., Park, Y. S., Powell, R., Lorenzi, P. L., Zheng, B., et al. (2022) · Figshare · doi:10.6084/m9.figshare.19218681
Additional file 12 of S6K1 amplification confers innate resistance to CDK4/6 inhibitors through activating c-Myc pathway in patients with estrogen receptor-positive breast cancer
Mo, H., Liu, X., Xue, Y., Chen, H., Guo, S., Li, Z., Wang, S., Li, C., Han, J., Fu, M., et al. (2022) · Figshare · doi:10.6084/m9.figshare.20745195
Additional file 1 of Combined inhibition of HMGCoA reductase and mitochondrial complex I induces tumor regression of BRAF inhibitor-resistant melanomas
de Groot, E., Varghese, S., Tan, L., Knighton, B. G., Sobieski, M. M., Nguyen, N., Park, Y. S., Powell, R., Lorenzi, P. L., Zheng, B., et al. (2022) · Figshare · doi:10.6084/m9.figshare.19218675
Additional file 2 of The potential of PARP as a therapeutic target across pediatric solid malignancies
Keller, K. M., Koetsier, J., Schild, L. G., Amo-Addae, V., Eising, S., van den Handel, K., Ober, K., Koopmans, B., Essing, A. H. W., van den Boogaard, M. L., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26580596
Additional file 1 of Combined targeting of MEK and the glucocorticoid receptor for the treatment of RAS-mutant multiple myeloma
Sriskandarajah, P., de Haven‐Brandon, A., Macleod, K., Carragher, N. O., Kirkin, V., Kaiser, M., & Whittaker, S. R. (2020) · Figshare · doi:10.6084/m9.figshare.12050766
Additional file 3 of Combined inhibition of HMGCoA reductase and mitochondrial complex I induces tumor regression of BRAF inhibitor-resistant melanomas
de Groot, E., Varghese, S., Tan, L., Knighton, B. G., Sobieski, M. M., Nguyen, N., Park, Y. S., Powell, R., Lorenzi, P. L., Zheng, B., et al. (2022) · Figshare · doi:10.6084/m9.figshare.19218687
Additional file 10 of S6K1 amplification confers innate resistance to CDK4/6 inhibitors through activating c-Myc pathway in patients with estrogen receptor-positive breast cancer
Mo, H., Liu, X., Xue, Y., Chen, H., Guo, S., Li, Z., Wang, S., Li, C., Han, J., Fu, M., et al. (2022) · Figshare · doi:10.6084/m9.figshare.20745186
Additional file 1 of S6K1 amplification confers innate resistance to CDK4/6 inhibitors through activating c-Myc pathway in patients with estrogen receptor-positive breast cancer
Mo, H., Liu, X., Xue, Y., Chen, H., Guo, S., Li, Z., Wang, S., Li, C., Han, J., Fu, M., et al. (2022) · Figshare · doi:10.6084/m9.figshare.20745201
Evaluating Synergy of Clinically Utilized Phage OMKO1 with Five Antibiotics from Different Classes against Pseudomonas aeruginosaPreprint
Kane, E. L., Chan, B., Mould, D. L., Kortright, K. E., Koff, J., & Turner, P. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.01.13.699299
“This is a notable feature of the Bliss independence model which distinguishes it from other commonly used models for determining synergy (34).”
Role of the ETV5/p38 Signaling Axis in Aggressive Thyroid Cancer Cells
Houl, J. H., Bagheri‐Yarmand, R., Kunnimalaiyaan, M., Mendez, P. M., Kidd, J. L., Dadbin, A., Ruiz-Jurado, A., Parekh, P. A., Henderson, Y. C., Chari, N. S., et al. (2025) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-25-0228 · Cited by 1
“Synergy Scores were obtained by comparing the experimentally observed dose response surface to the theoretical surface and calculated using the difference from Bliss (32,46)(Supplementary Table S5).”
S6K1 Amplification Drives Primary Resistance to CDK4/6 Inhibitors via c-Myc Pathway Activation in Estrogen Receptor–Positive Breast Cancer
Miller, J. M., Fernandez, K. C., Moore, P. I., Smith, O. G., Sharma, A., & Tanaka, A. (2025) · Asian journal of Current Research in Clinical Cancer · doi:10.51847/mugzdk6vzb
Daraxonrasib (RMC-6236) is an effective targeted therapy for RAS -mutant neuroblastomaPreprint
Hill, R. D., Dalton, K. M., Kurupi, R., Slaughter, J. M., Roberts, J., Xing, Y., Kehinde, V., Zhang, K., Hu, B., Kraskauskiene, V., et al. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.02.19.706849
Emerging Synergistic Antimicrobial Combinations against Cholera
Bhagya Jyothi, J. L., & Dhanasingh, I. (2026) · Current Drug Therapy · doi:10.2174/0115748855422349251110071056
Contrasting metabolic and physiological responses underlie rootstock-mediated tolerance to combined salinity and water-deficit stress in cv. SyrahPreprint
Reta, K., Lupo, Y., Sikron, N., Acuña, T., Lazarovitch, N., & Fait, A. (2026) · SSRN Electronic Journal · doi:10.2139/ssrn.6443060
Alectinib boosts anti-tumor efficacy of disialoganglioside 2 chimeric antigen receptor T cells in ALK-mutated neuroblastoma by suppressing programmed death-ligand 1
Sugitatsu, Y., Tomida, A., Suematsu, M., Inoue, T., Kubo, H., Nakazawa, Y., Yagyu, S., & Iehara, T. (2026) · British Journal of Cancer · doi:10.1038/s41416-026-03363-8
Caractérisation des sous-types de récepteurs nicotiniques neuronaux d'insectes et étude de la modulation de leurs profils pharmacologiques par les insecticides néonicotinoïdes
Cartereau, A. (2018) · doi:10.70675/08d17a9dz368fz4c64z9e5az9697f49e6eef

Authors: Zhao, W., Sachsenmeier, K., Zhang, L., Sult, E., Hollingsworth, R. E., & Yang, H.
Affiliations: AbbVie (United States) (US)
Corresponding author: Zhao, Wei
ORCID: Zhao, Wei
Sachsenmeier, Kris
Zhang, Lanju
Hollingsworth, Robert E.
Yang, Harry
Venue: SLAS Discovery
Publisher: Elsevier BV
Published: 2014-06
Volume: 19
Issue: 5
Pages: 817-821
ISSN: 2472-5552 (ISSN-L)
DOI: 10.1177/1087057114521867
OpenAlex: W1980181290
Cited by: 322
References: 14
Citations by year: 2026: 46 · 2025: 33 · 2024: 29 · 2023: 45 · 2022: 40 · 2021: 19 · 2020: 26 · 2019: 23 · 2018: 17 · 2017: 17 · 2016: 14 · 2015: 11 · 2014: 2
FWCI: 15.18
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by-nc-nd
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
creativecommons.org/licenses/by-nc-nd/4.0/ (vor, 2866 d)
Locations: SLAS DISCOVERY (publishedVersion, cc-by-nc-nd)
PubMed (publishedVersion)
Topics: Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Drug Discovery › Computational Drug Discovery Methods
Physical Sciences › Mathematics › Statistics and Probability › Statistical Methods in Clinical Trials
Social Sciences › Decision Sciences › Management Science and Operations Research › Optimal Experimental Design Methods
Keywords: Bliss independence model, drug synergy, drug-drug interactions, false positive reduction, epidermal growth factor receptor, IGF-1 receptor, drug combination screening
MeSH terms: Algorithms, Antineoplastic Agents, Carcinoma, Non-Small-Cell Lung, Dose-Response Relationship, Drug, Drug Combinations, Drug Interactions, Drug Synergism, Humans, Lung Neoplasms, Models, Chemical, Neoplasms, Regression Analysis, Technology, Pharmaceutical, Signal Transduction, Receptor, IGF Type 1, Drug Resistance, Neoplasm, ErbB Receptors

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review

A New Bliss Independence Model to Analyze Drug Combination Data

Abstract

Overview

Integrity signals

Verification

Claims the paper makes

Claims other papers make about this one

Citations

Cites

Cited by

Related

Metadata

Record

About these checks