(ChemotherapyAdvisor)– Administering chemotherapy sequentially, not simultaneously, may make cancercells less tumorigenic, according to researchers of Massachusetts Institute ofTechnology, Cambridge, MA, and Harvard University, Cambridge, MA. Thisconclusion is based on an article entitled “Sequential Application ofAnticancer Drugs Enhances Cell Death by Rewiring Apoptotic Signaling Networks,”which was published in Cell on May 11.

Thearticle is premised on the concepts of signal transduction crosstalk andcomplexity within signaling pathways, which occur in normal cells; thesefunctions are disrupted by the actions of oncogenes. The investigators soughtto perform a network analysis of the mechanisms of normal and oncogenicsignaling through the rewiring of pathways by anti-cancer drugs; this approachmay provide opportunities to target tumors with high specificity and efficacy,they wrote.

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Theinvestigators used targeted inhibition of oncogenic signaling pathways,combined with DNA-damaging chemotherapy to develop a new chemotherapeuticsequencing approach. They reported that “time-staggered EGFR inhibition, butnot simultaneous co-administration, dramatically sensitizes a subset oftriple-negative breast cancer cells to genotoxic drugs.”

Furthersystems-level analysis using temporal measurement of signaling networks, geneexpression, and cellular responses, in combination with mathematical modeling revealedthe approach necessary for drug-assisted rewiring of oncogenic signalingpathways. The approach makes normal cells less tumorigenic, reactivatesapoptotic pathways, and consequently makes cells more susceptible to DNAdamage-induced cell death.

The investigators concluded that the concept oftime-staggered inhibition will always be necessary to strengthen the efficacyof a given chemotherapeutic regimen and that using systems engineering torewire cell-signaling pathways can have a large potential impact on cancertreatment.