Integrated Network Pharmacology Approach for Drug Combination Discovery: A Multi‐Cancer Case Study

Antonio Federico, Michele Fratello, Giovanni Scala, Lena Möbus, Alisa Pavel, Giusy Del Giudice, Michele Ceccarelli, Valerio Costa, Alfredo Ciccodicola, Vittorio Fortino, Angela Serra, Dario Greco

Research output: Contribution to journalArticleScientificpeer-review


Despite remarkable efforts of computational and predictive pharmacology to improve therapeutic strategies for complex diseases, only in a few cases have the predictions been eventually employed in the clinics. One of the reasons behind this drawback is that current predictive approaches are based only on the integration of molecular perturbation of a certain disease with drug sensitivity signatures, neglecting intrinsic properties of the drugs. Here we integrate mechanistic and chemocentric approaches to drug repositioning by developing an innovative network pharmacology strategy. We developed a multilayer network‐based computational framework integrating perturbational signatures of the disease as well as intrinsic characteristics of the drugs, such as their mechanism of action and chemical structure. We present five case studies carried out on public data from The Cancer Genome Atlas, including invasive breast cancer, colon adenocarcinoma, lung squamous cell carcinoma, hepatocellular carcinoma and prostate adenocarcinoma. Our results highlight paclitaxel as a suitable drug for combination therapy for many of the considered cancer types. In addition, several non‐cancer‐related genes representing unusual drug targets were identified as potential candidates for pharmacological treatment of cancer.

Original languageEnglish
Article number2043
Number of pages16
Issue number8
Publication statusPublished - Apr 2022
Publication typeA1 Journal article-refereed


  • cancer
  • cancer therapy
  • drug combinations
  • drug repositioning
  • druggability
  • network
  • systems pharmacology

Publication forum classification

  • Publication forum level 1

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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