MEK1/2 inhibitors AS703026 and AZD6244 may be potential therapies for KRAS mutated colorectal cancer that is resistant to EGFR monoclonal antibody therapy (Cancer Res, 2011, 71:445-453)

報告日期: 2011/03/04
報告時間: 15:10/16:00
報告學生: 賴泰佑 (英文報告)
講評老師: 洪澤民
附件下載:

Full Text: http://basicmed.med.ncku.edu.tw/admin/up_img/0304-1.pdf

MEK1/2 Inhibitors AS703026 and AZD6244 May Be Potential Therapies for KRAS Mutated Colorectal Cancer That Is Resistant to EGFR Monoclonal Antibody Therapy

Juyong Yoon, Kyoung-Hwa Koo, and Kang-Yell Choi

Cancer Res. 2011 Jan 15;71(2):445-53. Epub 2010 Nov 30.

 

Speaker: 賴泰佑

Commentator: 洪澤民 老師

Date: 15:10 – 16:00 March 4, 2011

Place: Room 602, College of Medicine

 

Background

        The treatment of metastatic colorectal cancer, including chemotherapy and EGFR-targeted therapy, increases the median overall survival time from 12 to 21 months during the past decade. However, there are still a portion (8~23%) of patients, bearing K-ras activating mutations, who are resistant to the treatment of anti-EGFR monoclonal antibody (mAb) therapy, such as cetuximab (Erbitux).

        The anti-EGFR mAb, cetuximab, binding to the extracellular domain of EGFR, prevents ligand binding and inhibits signaling cascades, such as Ras-Raf-MEK-ERK and PI3K-Akt pathways. The K-ras activating mutation stimulates cell proliferation via the Raf-MEK-ERK pathway and blocks the effect of cetuximab. Thus, inhibition of MEK may be the therapeutic target of K-ras mutated colorectal cancer.

Objective

        MEK inhibition may overcome anti-EGFR mAb resistance attributed to K-ras mutations in some colorectal cancers.

Results

        There are two MEK inhibitors, AS703026 and AZD6244, which are undergoing clinical trial-phase I and phase II, respectively. The two MEK inhibitors were tested on isogenic human colorectal tumor cell lines that expressed only WT or mutant K-Ras (D-WT or D-MUT). Compared to cetuximab, which only can inhibit cell growth on D-WT cells, MEK inhibitors are effective in inhibiting tumor cell growth on the D-MUT cells both in vitro and in vivo.

Conclusion

        MEK inhibitors can be effective therapies to treat K-ras mutated colorectal cancer.

 

Reference1-3

1.    Downward, J. Targeting RAS signalling pathways in cancer therapy. Nat Rev Cancer 3, 11-22 (2003).

2.    Di Fiore, F., et al. Clinical relevance of KRAS mutation detection in metastatic colorectal cancer treated by Cetuximab plus chemotherapy. Br J Cancer 96, 1166-1169 (2007).

3.    Fremin, C. & Meloche, S. From basic research to clinical development of MEK1/2 inhibitors for cancer therapy. J Hematol Oncol, 3-8 (2010).