Combination therapy in combating cancer

Mokhtari, Reza Bayat; Homayouni, Tina S.; Baluch, Narges; Morgatskaya, Evgeniya; Kumar, Sushil; Das, Bikul; Yeger, Herman

doi:10.18632/oncotarget.16723

Cited by 2,543Cancer, Hypoxia, and MetabolismEnzyme function and inhibitionCancer Cells and Metastasis

Combination therapy in combating cancer

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Mokhtari, Reza Bayat, Homayouni, Tina S., Baluch, Narges, Morgatskaya, Evgeniya, Kumar, Sushil, Das, Bikul, Yeger, Herman·2017·Oncotarget

DOI 10.18632/oncotarget.16723PMC PMC5514969

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Abstract

// Reza Bayat Mokhtari 1,2,4 , Tina S. Homayouni 1 , Narges Baluch 3 , Evgeniya Morgatskaya 1 , Sushil Kumar 1 , Bikul Das 4 and Herman Yeger 1,2 1 Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, Ontario, Canada 2 Department of Paediatric Laboratory Medicine, The Hospital for Sick Children and Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada 3 Department of Pathology and Molecular Medicine, Queen’s University, Kingston, Ontario, Canada 4 Department of Immunology and Infectious Diseases, The Forsyth Institute, Cambridge, Massachusetts, USA Correspondence to: Herman Yeger, email: // Reza Bayat Mokhtari, email: // Keywords : Nrf2-Keap1, HIF-1alpha, carbonic anhydrase 9 (CAIX), histone deacetylase inhibitor (HDACi), carbonic anhydrase inhibitor (CAI) Received : October 19, 2016 Accepted : February 27, 2017 Published : March 30, 2017 Abstract Combination therapy, a treatment modality that combines two or more therapeutic agents, is a cornerstone of cancer therapy. The amalgamation of anti-cancer drugs enhances efficacy compared to the mono-therapy approach because it targets key pathways in a characteristically synergistic or an additive manner. This approach potentially reduces drug resistance, while simultaneously providing therapeutic anti-cancer benefits, such as reducing tumour growth and metastatic potential, arresting mitotically active cells, reducing cancer stem cell populations, and inducing apoptosis. The 5-year survival rates for most metastatic cancers are still quite low, and the process of developing a new anti-cancer drug is costly and extremely time-consuming. Therefore, new strategies that target the survival pathways that provide efficient and effective results at an affordable cost are being considered. One such approach incorporates repurposing therapeutic agents initially used for the treatment of different diseases other than cancer. This approach is effective primarily when the FDA-approved agent targets similar pathways found in cancer. Because one of the drugs used in combination therapy is already FDA-approved, overall costs of combination therapy research are reduced. This increases cost efficiency of therapy, thereby benefiting the “medically underserved”. In addition, an approach that combines repurposed pharmaceutical agents with other therapeutics has shown promising results in mitigating tumour burden. In this systematic review, we discuss important pathways commonly targeted in cancer therapy. Furthermore, we also review important repurposed or primary anti-cancer agents that have gained popularity in clinical trials and research since 2012.

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Single-drug therapy is typically inadequate for patients with advanced disease, leading to rapid disease progression and poor clinical outcomes.
“Moreover, single-drug therapy is typically inadequate for patients with advanced disease, leading to rapid disease progression and poor clinical outcomes [17].”
From Advances in platinum-based cancer therapy: overcoming platinum resistance through rational combinatorial strategies (2025) · cites this paper as [17]
The Background (page unavailable) says monotherapy is generally less effective than combination therapy and more susceptible to drug resistance. The Abstract notes low survival rates for most metastatic cancers, but the paper does not establish that single-drug therapy typically causes rapid progression and poor clinical outcomes specifically in patients with advanced disease. (LLM, conf=0.86)
Experimental — accuracy not yet measured
Additive and/or synergistic relationships can convert less effective single-drug treatments into regimens with robust anti-tumour activity.
“Specifically, additive and/or synergistic relationships can convert less effective single-drug treatments into regimens with robust anti-tumour activity [17].”
From Advances in platinum-based cancer therapy: overcoming platinum resistance through rational combinatorial strategies (2025) · cites this paper as [17]
Due to redundancy of signals that control tumor growth, drug combinations targeting multiple key nodes in growth-promoting signaling pathways have led to increasing FDA approvals.
“Due to the redundancy of signals that control tumor growth, drug combinations targeting multiple key nodes in growth-promoting signaling pathways has led to increasing Food and Drug Administration (FDA) approvals.75,76”
From Overcoming Resistance to Drugs Targeting KRAS Mutation (2020) · cites this paper as [76]
Using two or more inhibitors would significantly increase toxicity if they non-selectively act on normal cells and cancer cells.
“The caveat with combination therapies is that using two or more inhibitors would significantly increase toxicity if they non-selectively act on normal cells and cancer cells.76,82”
From Overcoming Resistance to Drugs Targeting KRAS Mutation (2020) · cites this paper as [76]

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Authors: Mokhtari, R. B., Homayouni, T. S., Baluch, N., Morgatskaya, E., Kumar, S., Das, B., & Yeger, H.
Affiliations: University of Toronto (CA)
Hospital for Sick Children (CA)
Queen's University (CA)
The Forsyth Institute (US)
ORCID: Kumar, Sushil
Das, Bikul
Yeger, Herman
Venue: Oncotarget
Publisher: Impact Journals, LLC
Published: 2017-03-30
Volume: 8
Issue: 23
Pages: 38022-38043
ISSN: 1949-2553 (ISSN-L)
DOI: 10.18632/oncotarget.16723
PMC: PMC5514969
OpenAlex: W2600452401
Cited by: 2,543
References: 185
Citations by year: 2026: 218 · 2025: 397 · 2024: 424 · 2023: 396 · 2022: 322 · 2021: 338 · 2020: 233 · 2019: 136 · 2018: 64 · 2017: 6 · 2015: 1
FWCI: 12.28
Type: journal article
Language: en
Open access: diamond
doi.org
Licence: cc-by
Locations: Oncotarget (publishedVersion, cc-by)
Europe PMC (PubMed Central) (publishedVersion, cc-by)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Enzyme function and inhibition
Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
Keywords: combination therapy, anticancer drug repurposing, Nrf2/Keap1 pathway, HIF-1α, carbonic anhydrase IX, histone deacetylase inhibitors, carbonic anhydrase inhibitors, drug resistance, cancer stem cells, apoptosis, metastasis, synergistic drug combination, anticancer drug targets, FDA-approved drugs
MeSH terms: Antineoplastic Agents, Carbonic Anhydrase Inhibitors, Humans, Neoplasms, Survival Rate

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