Staggering Chemotherapies May Impact Disease Progression

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

The article is premised on the concepts of signal transduction crosstalk and complexity within signaling pathways, which occur in normal cells; these functions are disrupted by the actions of oncogenes. The investigators sought to perform a network analysis of the mechanisms of normal and oncogenic signaling through the rewiring of pathways by anti-cancer drugs; this approach may provide opportunities to target tumors with high specificity and efficacy, they wrote.

The investigators used targeted inhibition of oncogenic signaling pathways, combined with DNA-damaging chemotherapy to develop a new chemotherapeutic sequencing approach. They reported that “time-staggered EGFR inhibition, but not simultaneous co-administration, dramatically sensitizes a subset of triple-negative breast cancer cells to genotoxic drugs.”

Further systems-level analysis using temporal measurement of signaling networks, gene expression, and cellular responses, in combination with mathematical modeling revealed the approach necessary for drug-assisted rewiring of oncogenic signaling pathways. The approach makes normal cells less tumorigenic, reactivates apoptotic pathways, and consequently makes cells more susceptible to DNA damage-induced cell death.

The investigators concluded that the concept of time-staggered inhibition will always be necessary to strengthen the efficacy of a given chemotherapeutic regimen and that using systems engineering to rewire cell-signaling pathways can have a large potential impact on cancer treatment.


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