Influence networks based on coexpression improve drug target discovery for the development of novel cancer therapeutics.
BACKGROUND
The demand for novel molecularly targeted drugs will continue to rise as we move forward toward the goal of personalizing cancer treatment to the molecular signature of individual tumors. However, the identification of targets and combinations of targets that can be safely and effectively modulated is one of the greatest challenges facing the drug discovery process. A promising approach is to use biological networks to prioritize targets based on their relative positions to one another, a property that affects their ability to maintain network integrity and propagate information-flow. Here, we introduce influence networks and demonstrate how they can be used to generate influence scores as a network-based metric to rank genes as potential drug targets.


RESULTS
We use this approach to prioritize genes as drug target candidates in a set of ER⁺ breast tumor samples collected during the course of neoadjuvant treatment with the aromatase inhibitor letrozole. We show that influential genes, those with high influence scores, tend to be essential and include a higher proportion of essential genes than those prioritized based on their position (i.e. hubs or bottlenecks) within the same network. Additionally, we show that influential genes represent novel biologically relevant drug targets for the treatment of ER⁺ breast cancers. Moreover, we demonstrate that gene influence differs between untreated tumors and residual tumors that have adapted to drug treatment. In this way, influence scores capture the context-dependent functions of genes and present the opportunity to design combination treatment strategies that take advantage of the tumor adaptation process.


CONCLUSIONS
Influence networks efficiently find essential genes as promising drug targets and combinations of targets to inform the development of molecularly targeted drugs and their use.
Nadia M
NM
Penrod
Department of Genetics, Geisel School of Medicine at Dartmouth College, HB7937 One Medical Center Dr,, Lebanon, NH 03766, USA. jason.h.moore@dartmouth.edu.
Jason H
JH
Moore
D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D019295:Computational Biology / Q000379:methods*; D055808:Drug Discovery / Q000379:methods*; D020869:Gene Expression Profiling; D006801:Humans; D000077289:Letrozole; D058990:Molecular Targeted Therapy / Q000379:methods*; D009570:Nitriles / Q000494:pharmacology / Q000627:therapeutic use; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D014230:Triazoles / Q000494:pharmacology / Q000627:therapeutic use
D000970:Antineoplastic Agents; D009570:Nitriles; D012333:RNA, Messenger; D011960:Receptors, Estrogen; D014230:Triazoles; D000077289:Letrozole