- BRAFインヒビター(PLX4032 (vemurafenib) )を転移性メラノーマに使うと効果は目覚ましいが、そのうち二次癌を引き起こすことが最近の話題である。
- BRAF(V600E) 変異大腸癌が一定の割合で発症するが、それらにはBRAFインヒビター(PLX4032 (vemurafenib) )は効果がない。
- メラノーマと大腸癌の違いはEGFRの発現ーEGFR依存性によるという。
- 二次癌として大腸癌が起こらない理由にもEGFRが関与するということなのだろうか?
- 組織特異的発癌を考える上で、極めて面白い題材を私たちは今手にしているということなのだと思う。
Nature
Received 28 September 2011
Accepted 18 January 2012
Published online 26 January 2012
Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR
- Inhibition of the BRAF(V600E) oncoprotein by the small-molecule drug PLX4032 (vemurafenib) is highly effective in the treatment of melanoma1. However, colon cancer patients harbouring the same BRAF(V600E) oncogenic lesion have poor prognosis and show only a very limited response to this drug2, 3, 4. To investigate the cause of the limited therapeutic effect of PLX4032 in BRAF(V600E) mutant colon tumours, here we performed an RNA-interference-based genetic screen in human cells to search for kinases whose knockdown synergizes with BRAF(V600E) inhibition. We report that blockade of the epidermal growth factor receptor (EGFR) shows strong synergy with BRAF(V600E) inhibition. We find in multiple BRAF(V600E) mutant colon cancers that inhibition of EGFR by the antibody drug cetuximab or the small-molecule drugs gefitinib or erlotinib is strongly synergistic with BRAF(V600E) inhibition, both in vitro and in vivo. Mechanistically, we find that BRAF(V600E) inhibition causes a rapid feedback activation of EGFR, which supports continued proliferation in the presence of BRAF(V600E) inhibition. Melanoma cells express low levels of EGFR and are therefore not subject to this feedback activation. Consistent with this, we find that ectopic expression of EGFR in melanoma cells is sufficient to cause resistance to PLX4032. Our data suggest that BRAF(V600E) mutant colon cancers (approximately 8–10% of all colon cancers2, 3, 5), for which there are currently no targeted treatment options available, might benefit from combination therapy consisting of BRAF and EGFR inhibitors.
最近BRAF抑制剤にこだわっているので、しばらくこの路線を探求したい。面白いテーマであるぞ、メラノーマと大腸癌。
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