This week’s New England Journal of Medicine (NEJM) contained a fascinating article on how a specific gene mutation known as Transcription factor AP-2 epsilon, TFAP2E–DKK4, appears to be responsible for inducing at least some of the resistance to chemotherapy that occurs during treatment of colon cancer.

At first sight, I wasn’t sure from the abstract if they were referring to either adaptive resistance to therapy or whether genetic changes already present limited the effectivenes of the treatment.

Further reading of the full article more specifically pointed to the latter:

“Epigenetic alterations underlying the pathogenesis of colorectal cancer have been reported by several groups. These alterations include hypomethylation and hypermethylation of DNA as well as histone modifications, all of which have a profound effect on transcriptional gene regulation. The role of these molecular alterations in response prediction and treatment resistance are far less well known.”

For readers interested in more background on histone modifications, check out a previous post on epigenetics first.

What did this research show?

There were a couple of interesting findings in this study, which involved both cell lines and also cancer patients:

“TFAP2E was hypermethylated in 38 of 74 patients (51%) in the initial cohort. Hypermethylation was associated with decreased expression of TFAP2E in primary and metastatic colorectal-cancer specimens and cell lines. Colorectal-cancer cell lines overexpressing DKK4 showed increased chemoresistance to fluorouracil but not irinotecan or oxaliplatin.”

Fluorouracil (5FU) is one of the key bedrocks of chemotherapy when combined with either oxaliplatin (as FOLFOX) or irinotecan (as FOLFIRI), so any epigenetic changes present that limit it’s effectiveness will have a negative impact on the overall treatment response.

The impact of DKK4 was first shown in cell lines by Xi et al., (2006), but this is the first time I think it has been reported in human patients with colon cancer. The research also uncovered some other important findings:

“In the four other patient cohorts, TFAP2E hypermethylation was significantly associated with nonresponse to chemotherapy (P<0.001).”

I’d like to see these results validated on a larger scale, but if replicable, they will have a huge potential impact on clinical practice. If a patient is found to have the TFAP2E mutation, then there will be little point in exposing them to the rigours of chemotherapy with their not inconsiderable side effects if there is little chance of response. A clinical trial or other alternatives such as targeted therapies (EGFR, VEGF) might be a better option in this case.

“Conversely, the probability of response among patients with hypomethylation was approximately six times that in the entire population (overall estimated risk ratio, 5.74; 95% confidence interval, 3.36 to 9.79).”

It’s amazing how just a small change (hypo = positive, hyper = negative in this particular example) can have an enormous potential impact on the probability of response to chemotherapy.

Because the TFAP2E-dependent resistance was found to be mediated through DKK4, the authors suggested that patients who have colorectal cancer with TFAP2E hypermethylation could be approached differently. In other words:

“Specific targeting of DKK4 in these individuals may therefore be an option for overcoming TFAP2E-mediated chemoresistance.”

That, however, may be easier said than done and here’s why – DKK4, or Dickkopf 4, is associated with canonical Wnt signalling and beta-catenin/Tcf-4, which is not the easiest thing to target using currently available approaches. It may be a little while before we see some progress on the R&D front, but certainly the good news is that we at least have some valid targets to aim at.

What do these results mean?

It has long been known that patients vary considerably in their response to treatment and what this research clearly shows us is that genetic changes, specifically the presence of the TFAP2E–DKK4 mutation may explain why some patients with colorectal cancer fare better with chemotherapy than others. In other words, it portends a poorer prognosis and overall response to treatment.

It will be interesting to see if new epigenetic therapies develop in the near future to try and essentially overcome and reverse the histone modifications that impact the treatment response.

References:

rb2 large gray Gene mutation and resistance to chemotherapy in colorectal cancerEbert, M., Tänzer, M., Balluff, B., Burgermeister, E., Kretzschmar, A., Hughes, D., Tetzner, R., Lofton-Day, C., Rosenberg, R., Reinacher-Schick, A., Schulmann, K., Tannapfel, A., Hofheinz, R., Röcken, C., Keller, G., Langer, R., Specht, K., Porschen, R., Stöhlmacher-Williams, J., Schuster, T., Ströbel, P., & Schmid, R. (2012). TFAP2E–DKK4 and Chemoresistance in Colorectal Cancer New England Journal of Medicine, 366 (1), 44-53 DOI: 10.1056/NEJMoa1009473

Xi, Y., Nakajima, G., Schmitz, J., Chu, E., & Ju, J. (2006). Multi-level gene expression profiles affected by thymidylate synthase and 5-fluorouracil in colon cancer BMC Genomics, 7 (1) DOI: 10.1186/1471-2164-7-68