Identification of the MEK1(F129L) activating mutation as a potential mechanism of acquired resistance to MEK inhibition in human cancers carrying the B-Raf V600E mutation Journal Article
| Authors: | Wang, H.; Daouti, S.; Li, W. H.; Wen, Y.; Rizzo, C.; Higgins, B.; Packman, K.; Rosen, N.; Boylan, J. F.; Heimbrook, D.; Niu, H. |
| Article Title: | Identification of the MEK1(F129L) activating mutation as a potential mechanism of acquired resistance to MEK inhibition in human cancers carrying the B-Raf V600E mutation |
| Abstract: | Although targeting the Ras/Raf/MEK pathway remains a promising anticancer strategy, mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase (MEK) inhibitors in clinical development are likely to be limited in their ability to produce durable clinical responses due to the emergence of acquired drug resistance. To identify potential mechanisms of such resistance, we established MEK inhibitor - resistant clones of human HT-29 colon cancer cells (HT-29R cells) that harbor the B-Raf V600E mutation. HT-29R cells were specifically resistant to MEK inhibition in vitro and in vivo, with drug-induced elevation of MEK/ERK and their downstream targets primarily accountable for drug resistance. We identified MEK1(F129L) mutation as a molecular mechanism responsible for MEK/ERK pathway activation. In an isogenic cell system that extended these findings into other cancer cell lines, the MEK1(F129L) mutant exhibited higher intrinsic kinase activity than wild-type MEK1 [MEK1(WT)], leading to potent activation of ERK and downstream targets. The MEK1(F129L) mutation also strengthened binding to c-Raf, suggesting an underlying mechanism of higher intrinsic kinase activity. Notably, the combined use of Raf and MEK inhibitors overcame the observed drug resistance and exhibited greater synergy in HT-29R cells than the drug-sensitive HT-29 parental cells. Overall, our findings suggested that mutations in MEK1 can lead to acquired resistance in patients treated with MEK inhibitors and that a combined inhibition of Raf and MEK may be potentially useful as a strategy to bypass or prevent drug resistance in the clinic. ©2011 AACR. |
| Keywords: | mitogen activated protein kinase; controlled study; protein expression; treatment outcome; unclassified drug; gene mutation; human cell; sorafenib; doxorubicin; raf protein; dose response; nonhuman; paclitaxel; antineoplastic agent; mouse; drug inhibition; mitogen activated protein kinase kinase 1; mitogen activated protein kinase kinase 2; mitogen activated protein kinase inhibitor; molecular dynamics; animal experiment; animal model; in vivo study; enzyme activation; in vitro study; enzyme activity; wild type; irinotecan; oncogene; colon cancer; cancer cell; b raf kinase; n (2,3 dihydroxypropoxy) 3,4 difluoro 2 (2 fluoro 4 iodoanilino)benzamide; b raf kinase inhibitor; plx 4720; vemurafenib; c raf kinase; d 0325901; mitogen activated protein kinase kinase inhibitor; ro 4927350; ro 4987655; oncogene b raf |
| Journal Title: | Cancer Research |
| Volume: | 71 |
| Issue: | 16 |
| ISSN: | 0008-5472 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2011-08-15 |
| Start Page: | 5535 |
| End Page: | 5545 |
| Language: | English |
| DOI: | 10.1158/0008-5472.can-10-4351 |
| PROVIDER: | scopus |
| PUBMED: | 21705440 |
| DOI/URL: | |
| Notes: | --- - "Export Date: 3 October 2011" - "CODEN: CNREA" - "Source: Scopus" |
