The DOI matches its Crossref record; 172 of the 172 references it cites were found in a registry or an index.
Combinatorial drug therapy for cancer in the post-genomic era
Abstract
Over the past decade, whole genome sequencing and other 'omics' technologies have defined pathogenic driver mutations to which tumor cells are addicted. Such addictions, synthetic lethalities and other tumor vulnerabilities have yielded novel targets for a new generation of cancer drugs to treat discrete, genetically defined patient subgroups. This personalized cancer medicine strategy could eventually replace the conventional one-size-fits-all cytotoxic chemotherapy approach. However, the extraordinary intratumor genetic heterogeneity in cancers revealed by deep sequencing explains why de novo and acquired resistance arise with molecularly targeted drugs and cytotoxic chemotherapy, limiting their utility. One solution to the enduring challenge of polygenic cancer drug resistance is rational combinatorial targeted therapy.
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“Combination therapies using two or more therapeutic agents can be superior to single-agent therapies in the treatment of cancers (1–3).”
From Statistical Assessment of Drug Synergy from In Vivo Combination Studies Using Mouse Tumor Models (2023) · cites this paper as [1]
In the citing paper
“combinations of inhibitors targeting multiple effector and/or feedback pathways have shown impressive activity in KRAS mutant model systems”
From A Landscape of Therapeutic Cooperativity in KRAS Mutant Cancers Reveals Principles for Controlling Tumor Evolution (2017) · cites this paper as Al-Lazikani et al., 2012
In the citing paper
“The activity of single agent therapies targeting individual RAS effector pathways is limited”
From A Landscape of Therapeutic Cooperativity in KRAS Mutant Cancers Reveals Principles for Controlling Tumor Evolution (2017) · cites this paper as Al-Lazikani et al., 2012
In the citing paper
“To minimize the emergence of resistant clones and to achieve maximal therapeutic response, combinations of different classes of therapeutic agents123 are commonly used.”
From MDM2, MDMX and p53 in oncogenesis and cancer therapy (2013) · cites this paper as [123]
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“The rational combination of two or more targeted agents is based on genomic profiling of single tumors that may identify the primary driver oncogene and key targets in possible compensatory mechanisms (5, 7).”
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“One possible solution for this situation is to use CRISPR technology to silence MDR genes and increase cancer treatment effectiveness (1).”
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Combinatorial perturbation sequencing on single cells using microwell-based droplet random pairing
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Perspective on the dynamics of cancer
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“In any case, the evolving genetic heterogeneity of tumors will remain a serious challenge to the development of an effective cancer therapy through the combination of multiple drugs [19, 21].”
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“Since single drug therapy is prone to cause drug resistance, it is currently popular for the scientists and clinicians to explore efficient drug combination therapies from the list of existing drugs [3–5], which not only can increase treatment efficacy and reduce toxicity, but also produce a better therapeutic outcome…”
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“Currently, the main way to solve this problem is to synergistically act on cancer cells through drug combinations [35].”
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BackgroundRECOVER identifies synergistic drug combinations in vitro through sequential model optimization
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BackgroundEssentiality and Transcriptome-Enriched Pathway Scores Predict Drug-Combination Synergy
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“An exponentially growing number of combination drugs, heterogeneous disease mechanisms, and cell cultural models challenge the capacity of experimentation to assess drugs [11], so rapid and e ffi cacious computational approaches could play a critical complementary role in their evaluation [12].”
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“In spite of the successes of combinatorial therapies, most of them were derived from the clinical experience and serendipitous discovery, only covering a tiny fraction of the large-scale combinatorial space (Al-Lazikani et al., 2012).”
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Screening of Drug Repositioning Candidates for Castration Resistant Prostate Cancer
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“The cytotoxic chemotherapy is most effective when given in combination to achieve an additive or synergistic effect and a targeted therapy involving more than one drug increases powerful antitumor effects and overcomes resistance mechanisms (61).”
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“And with the increasing concerns on multi-target therapeutics [62,63], we believe that our method can be further developed and help to design high-efficient combinatorial therapies for complex diseases.”
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“Synergistic combination therapy is critical to overcome primary and secondary drug resistance to targeted anticancer drugs (17).”
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Two-dimensional metal organic frameworks in cancer treatment
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Cytochrome P450 Bioconjugate as a Nanovehicle for Improved Chemotherapy Treatment
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Dendrogenin A Enhances Anti-Leukemic Effect of Anthracycline in Acute Myeloid Leukemia
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“Here, we show that the combination of DDA with a DNA-damaging agent potentiates AML cell-killing, showing that the multiple-cell-death mechanism improves the yield of AML cell-killing, supporting the AL-lazikani’s hypothesis [25].”
The oncogene-dependent resistance to reprogramming unveils cancer therapeutic targets
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Precision Medicine and Distributive Justice
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A simple gene set-based method accurately predicts the synergy of drug pairs
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“Response to combinatorial drug therapy is optimized when a drug combination achieves greater (synergistic) effects than independent effects [1].”
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Background
Metadata
- Authors
- Al-Lazikani, B., Banerji, U., & Workman, P.
- Affiliations
- Royal Marsden NHS Foundation Trust (GB)
- Institute of Cancer Research (GB)
- Corresponding author
- Banerji, Udai
- Workman, Paul
- Venue
- Nature Biotechnology
- Published
- 2012-07
- Volume
- 30
- Issue
- 7
- Pages
- 679-692
- ISSN
- 0733-222X (ISSN-L)
- 1087-0156
- 1546-1696
- OpenAlex
- W2061061337
- Cited by
- 1,070
- References
- 172
- Citations by year
- 2026: 63 · 2025: 80 · 2024: 71 · 2023: 73 · 2022: 87 · 2021: 73 · 2020: 80 · 2019: 91 · 2018: 81 · 2017: 76 · 2016: 83 · 2015: 90 · 2014: 69 · 2013: 46 · 2012: 6
- FWCI
- 5.04
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Biotechnology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- NIHR Biomedical Research Centre, Royal Marsden NHS Foundation Trust/Institute of Cancer Research
- Cancer Research UK (C309/8992, 11566, C309/A8274)
- National Institute for Health and Care Research
- National Institutes of Health
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Keywords
- combination therapy, targeted cancer therapy, driver mutations, synthetic lethality, tumor vulnerability, precision oncology, acquired drug resistance, de novo resistance, polygenic resistance, cytotoxic chemotherapy
- MeSH terms
- Antineoplastic Combined Chemotherapy Protocols, Clinical Trials as Topic, Combined Modality Therapy, Humans, Neoplasms, Drug Design, Genome, Human, Genetic Heterogeneity, Metabolic Networks and Pathways, Precision Medicine, Molecular Targeted Therapy, High-Throughput Nucleotide Sequencing
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