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Cancer Res. 2015 Jul 15;75(14):2851-62. doi: 10.1158/0008-5472.CAN-14-1623. Epub 2015 May 14.

Enhanced MET Translation and Signaling Sustains K-Ras-Driven Proliferation under Anchorage-Independent Growth Conditions.

Author information

1
Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California. Oncology Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan.
2
Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California.
3
Department of Pathology, University of California San Francisco, San Francisco, California.
4
Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California. mccormic@cc.ucsf.edu.

Abstract

Oncogenic K-Ras mutation occurs frequently in several types of cancers, including pancreatic and lung cancers. Tumors with K-Ras mutation are resistant to chemotherapeutic drugs as well as molecular targeting agents. Although numerous approaches are ongoing to find effective ways to treat these tumors, there are still no effective therapies for K-Ras mutant cancer patients. Here we report that K-Ras mutant cancers are more dependent on K-Ras in anchorage-independent culture conditions than in monolayer culture conditions. In seeking to determine mechanisms that contribute to the K-Ras dependency in anchorage-independent culture conditions, we discovered the involvement of Met in K-Ras-dependent, anchorage-independent cell growth. The Met signaling pathway is enhanced and plays an indispensable role in anchorage-independent growth even in cells in which Met is not amplified. Indeed, Met expression is elevated under anchorage-independent growth conditions and is regulated by K-Ras in a MAPK/ERK kinase (MEK)-dependent manner. Remarkably, in spite of a global downregulation of mRNA translation during anchorage-independent growth, we find that Met mRNA translation is specifically enhanced under these conditions. Importantly, ectopic expression of an active Met mutant rescues K-Ras ablation-derived growth suppression, indicating that K-Ras-mediated Met expression drives "K-Ras addiction" in anchorage-independent conditions. Our results indicate that enhanced Met expression and signaling is essential for anchorage-independent growth of K-Ras mutant cancer cells and suggests that pharmacological inhibitors of Met could be effective for K-Ras mutant tumor patients.

PMID:
25977330
PMCID:
PMC4506276
DOI:
10.1158/0008-5472.CAN-14-1623
[Indexed for MEDLINE]
Free PMC Article

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