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Gene mutation may explain chemoresistance in colon cancer
Ebert M. N Engl J Med. 2012;366:44-53.
A gene mutation may explain why some patients with advanced colorectal cancer are resistant to certain types of chemotherapy, according to researchers in Germany.
Researchers examined the expression and function of the gene encoding transcription factor AP-2 epsilon (TFAP2E) in nearly 300 patients who were undergoing chemotherapy or chemoradiation at six university hospitals.
When TFAP2E expression was low, expression of the gene encoding dickkopf homolog 4 protein (DKK4) — a downstream target gene of TFAP2E — was high. Cells with TFAP2E overexpression had DKK4 expression that was downgraded to an average of 17% of controls.
In the initial patient cohort, 38 of 74 patients showed TFAP2E hypermethylation, which was associated with decreased expression of TFAP2E in primary and metastatic colorectal-cancer specimens and cell lines.
Among the 38 patients with TFAP2E hypermethylation, researchers reported an increased resistance to fluorouracil-based chemotherapy compared with controls (P<.01) but no increased resistance to the chemotherapy drugs oxaliplatin (Eloxatin, Sanofi-Aventis) or irinotecan (Camptosar, Pfizer).
Among those with hypomethylation, or those with high TFAP2E expression, survival rates for cells exposed to fluorouracil were about 20% of control values (P<.01), researchers said.
In four subsequent cohorts totaling 220 patients, TFAP2E expression was significantly associated with nonresponse to chemotherapy with fluorouracil (P<.001), as patients with hypermethylation were nearly six times less likely to respond to fluorouracil than those with hypomethylation (RR=5.74; 95% CI, 3.36-9.79).
Overexpression of DKK4 — previously implicated in fluorouracil resistance — appeared to mediate the effect.
Researchers said most patients in the study had undergone combination chemotherapy, and tissue samples from patients undergoing fluorouracil-only treatment were not available.
“Since treatment strategies differed across the four cohorts of patients with colorectal cancer, alterations of TFAP2E-DKK4 not only may be associated with fluorouracil resistance but also could present a more global chemotherapy-resistance marker,” Matthias P.A. Ebert, MD, of Heidelberg University in Germany, and colleagues wrote.
Although the researchers said further studies are necessary to understand the precise molecular changes that lead to chemoresistance, the TFAP2E-DKK4 combination may help predict response and also provide an option for overcoming drug resistance in poor responders.
“Our data indicate that fluorouracil-based chemotherapy is largely ineffective in patients with colorectal cancer with TFAP2E hypermethylation,” they wrote. “Specific targeting of DKK4 in these individuals may therefore be an option for overcoming TFAP2E-mediated chemoresistance.”
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