Targeted drug combination therapy design based on driver genes

Lilian Zsákai, Anna Sipos, J. Dobos, Dániel Eros, Csaba Szántai-Kis, Péter Bánhegyi, János Pató, L. Őrfi, Zsolt Matula, G. Mikala, G. Kéri, I. Peták, István Vályi-Nagy

Research output: Contribution to journalArticle

Abstract

Targeted therapies against cancer types with more than one driver gene hold bright but elusive promise, since approved drugs are not available for all driver mutations and monotherapies often result in resistance. Targeting multiple driver genes in different pathways at the same time may provide an impact extensive enough to fight resistance. Our goal was to find synergistic drug combinations based on the availability of targeted drugs and their biological activity profiles and created an associated compound library based on driver gene-related protein targets. In this study, we would like to show that driver gene pattern based customized combination therapies are more effective than monotherapies on six cell lines and patient-derived primary cell cultures. We tested 55-102 drug combinations targeting driver genes and driver pathways for each cell line and found 25-85% of these combinations highly synergistic. Blocking 2-5 cancer pathways using only 2-3 targeted drugs was sufficient to reach high rates of tumor cell eradication at remarkably low concentrations. Our results demonstrate that the efficiency of cancer treatment may be significantly improved by combining drugs against multiple tumor specific drivers.

Original languageEnglish
Pages (from-to)5255-5266
Number of pages12
JournalOncotarget
Volume10
Issue number51
Publication statusPublished - Jan 1 2019

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Combination Drug Therapy
Genes
Drug Combinations
Neoplasms
Pharmaceutical Preparations
Cell Line
Primary Cell Culture
Drug Delivery Systems
Libraries
Therapeutics
Mutation
Proteins

Keywords

  • Cancer driver gene
  • Combination therapy
  • Multiple myeloma
  • Primary culture
  • Small molecule compound

ASJC Scopus subject areas

  • Oncology

Cite this

Zsákai, L., Sipos, A., Dobos, J., Eros, D., Szántai-Kis, C., Bánhegyi, P., ... Vályi-Nagy, I. (2019). Targeted drug combination therapy design based on driver genes. Oncotarget, 10(51), 5255-5266.

Targeted drug combination therapy design based on driver genes. / Zsákai, Lilian; Sipos, Anna; Dobos, J.; Eros, Dániel; Szántai-Kis, Csaba; Bánhegyi, Péter; Pató, János; Őrfi, L.; Matula, Zsolt; Mikala, G.; Kéri, G.; Peták, I.; Vályi-Nagy, István.

In: Oncotarget, Vol. 10, No. 51, 01.01.2019, p. 5255-5266.

Research output: Contribution to journalArticle

Zsákai, L, Sipos, A, Dobos, J, Eros, D, Szántai-Kis, C, Bánhegyi, P, Pató, J, Őrfi, L, Matula, Z, Mikala, G, Kéri, G, Peták, I & Vályi-Nagy, I 2019, 'Targeted drug combination therapy design based on driver genes', Oncotarget, vol. 10, no. 51, pp. 5255-5266.
Zsákai L, Sipos A, Dobos J, Eros D, Szántai-Kis C, Bánhegyi P et al. Targeted drug combination therapy design based on driver genes. Oncotarget. 2019 Jan 1;10(51):5255-5266.
Zsákai, Lilian ; Sipos, Anna ; Dobos, J. ; Eros, Dániel ; Szántai-Kis, Csaba ; Bánhegyi, Péter ; Pató, János ; Őrfi, L. ; Matula, Zsolt ; Mikala, G. ; Kéri, G. ; Peták, I. ; Vályi-Nagy, István. / Targeted drug combination therapy design based on driver genes. In: Oncotarget. 2019 ; Vol. 10, No. 51. pp. 5255-5266.
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