Chemotherapy Triggers Overexpression of a Drug Resistance Gene

Cancer researchers have identified a gene activated by chemotherapy and induce tumor cells to become drug resistant, which inevitably presents a poor prognosis for the patient.

Investigators at the University of Iowa (Iowa City, USA) and Brigham Young University (Provo, UT, USA) initially mapped genetic changes in a sequential series of tumor samples obtained from 19 myeloma patients undergoing intensive chemotherapy.

They reported in the January 14, 2013, issue of the journal Cancer Cell that the gene NEK2 (never in mitosis gene a-related kinase 2), a serine/threonine-protein kinase that is involved in mitotic regulation, was highly correlated with drug resistance, rapid relapse, and poor outcome. This protein is localized to the centrosome and undetectable during G1 phase, but accumulates progressively throughout the S phase, reaching maximal levels in late G2 phase.

Other studies revealed that NEK2 was overexpressed in many different types of cancer. Overexpression of NEK2 resulted in enhanced CIN (chromosomal instability, which occurs early in cancer development and is associated with poor prognosis), cell proliferation, and drug resistance. High expression of NEK2 induced drug resistance mainly through activation of the cancer cells' efflux pumps.

Targeting NEK2 by NEK2 shRNA (short hairpin RNA) overcame cancer cell-drug resistance and induced apoptosis in vitro and in a xenograft myeloma mouse model.

"Our studies show that over-expression of NEK2 in cancer cells significantly enhances the activity of drug efflux proteins to pump chemotherapy drugs out of cells, resulting in drug resistance. Furthermore, silencing NEK2 in cancer cells potently decreased drug resistance, induced cell-cycle arrest, cell death, and inhibited cancer cell growth in vitro and in vivo," said senior author Dr. Fenghuang Zhan, professor of internal medicine at the University of Iowa.

The investigators are now concentrating on the development of compounds to inhibit NEK2 activity.

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