Ras oncogenes: split personalities

Karnoub, Antoine E.; Weinberg, Robert A.

doi:10.1038/nrm2438

Cited by 1,319 publications

(1,304 citation statements)

References 223 publications

(194 reference statements)

Supporting

Mentioning

1,254

Contrasting

Unclassified

Order By: Relevance

“…While point mutations in codon 12 or 13 account for the majority of KRAS mutations (8), recent studies have reported that KRAS also undergoes copy number gain at chromosome 12p12 in 11% to 15% of lung tumors (9,10). RAS genes are members of the small GTPase super family (11) and function to propagate growth factor signaling through activation of c-RAF and phosphoinositide-3-kinase (PI3K) pathways. Despite concerted efforts, KRAS mutation defines a genetic subtype of lung cancer that is currently not amenable to therapeutic intervention (12).…”

Section: Introductionmentioning

confidence: 99%

Lactate Dehydrogenase B Is Required for the Growth of KRAS-Dependent Lung Adenocarcinomas

McCleland¹,

Adler²,

Deming³

et al. 2013

Clinical Cancer Research

111

View full text Add to dashboard Cite

Purpose: This study is aimed to identify genes within the KRAS genomic amplicon that are both coupregulated and essential for cell proliferation when KRAS is amplified in lung cancer.Experimental Design: We used an integrated genomic approach to identify genes that are coamplified with KRAS in lung adenocarcinomas and subsequently preformed an RNA interference (RNAi) screen to uncover functionally relevant genes. The role of lactate dehydrogenase B (LDHB) was subsequently investigated both in vitro and in vivo by siRNA and short hairpin RNA (shRNA)-mediated knockdown in a panel of lung adenocarcinoma cells lines. LDHB expression was also investigated in patient tumors using microarray and immunohistochemistry analyses.Results: RNAi-mediated depletion of LDHB abrogated cell proliferation both in vitro and in xenografted tumors in vivo. We find that LDHB expression correlates to both KRAS genomic copy number gain and KRAS mutation in lung cancer cell lines and adenocarcinomas. This correlation between LDHB expression and KRAS status is specific for lung cancers and not other tumor types that harbor KRAS mutations. Consistent with a role for LDHB in glycolysis and tumor metabolism, KRAS-mutant lung tumors exhibit elevated expression of a glycolysis gene signature and are more dependent on glycolysis for proliferation compared with KRAS wild-type lung tumors. Finally, high LDHB expression was a significant predictor of shorter survival in patients with lung adenocarcinomas.Conclusion: This study identifies LDHB as a regulator of cell proliferation in a subset of lung adenocarcinoma and may provide a novel therapeutic approach for treating lung cancer.

show abstract

Section: Introductionmentioning

confidence: 99%

Lactate Dehydrogenase B Is Required for the Growth of KRAS-Dependent Lung Adenocarcinomas

McCleland¹,

Adler²,

Deming³

et al. 2013

Clinical Cancer Research

111

View full text Add to dashboard Cite

show abstract

“…RAS-activating mutations, especially KRAS mutations, are one of the most prevalent genetic changes found in cancer, occurring in about 20% of human tumours (Downward, 2003;Karnoub and Weinberg, 2008). In these tumours, the activated RAS protein contributes significantly to several aspects of the malignant phenotype, including the deregulation of tumour cell growth, invasiveness and the ability to induce new blood-vessel formation, and the suppression of programmed cell death.…”

Section: Introductionmentioning

confidence: 99%

Critical role for transcriptional repressor Snail2 in transformation by oncogenic RAS in colorectal carcinoma cells

et al. 2010

View full text Add to dashboard Cite

Activating mutations in the KRAS gene are among the most prevalent genetic changes in human cancers. To identify synthetic lethal interactions in cancer cells harbouring mutant KRAS, we performed a large-scale screen in isogenic paired colon cancer cell lines that differ by a single allele of mutant KRAS using an inducible short hairpin RNA interference library. Snail2, a zinc finger transcriptional repressor encoded by the SNAI2 gene, was found to be selectively required for the long-term survival of cancer cells with mutant KRAS that have undergone epithelial-mesenchymal transition (EMT), a transdifferentiation event that is frequently seen in advanced tumours and is promoted by RAS activation. Snail2 expression is regulated by the RAS pathway and is required for EMT. Our findings support Snail2 as a possible target for the treatment of the broad spectrum of human cancers of epithelial origin with mutant RAS that have undergone EMT and are characterized by a high degree of chemoresistance and radioresistance.

show abstract

“…[1] Added to this, the experimental evidence substantiating the importance of the Ras-ERK pathway in cancer initiation and progression is overwhelming: activated mutants of Ras, Raf, and MEK have been shown to induce malignant transformation in many cell types. Studies using genetic and pharmacological interference of the Ras-ERK pathway have demonstrated that its signals are essential for the maintenance of the transformed phenotype in diverse tumor-derived cells, [1,2] and sophisticated animal models have endorsed the importance of this pathway for tumorigenesis in vivo. [3] Thus, it is hardly surprising that this signaling cascade has attracted enormous attention for antineoplastic intervention.…”

Section: Introductionmentioning

confidence: 99%

The Ras‐ERK pathway: Understanding site‐specific signaling provides hope of new anti‐tumor therapies

2010

View full text Add to dashboard Cite

Recent discoveries have suggested the concept that intracellular signals are the sum of multiple, site-specified subsignals, rather than single, homogeneous entities. In the context of cancer, searching for compounds that selectively block subsignals essential for tumor progression, but not those regulating ''house-keeping'' functions, could help in producing drugs with reduced side effects compared to compounds that block signaling completely. The Ras-ERK pathway has become a paradigm of how space can differentially shape signaling. Today, we know that Ras proteins are found in different plasma membrane microdomains and endomembranes. At these localizations, Ras is subject to site-specific regulatory mechanisms, distinctively engaging effector pathways and switching-on diverse genetic programs to generate different biological responses. The Ras effector pathway leading to ERKs activation is also under strict, space-related regulatory processes. These findings may open a gate for aiming at the Ras-ERK pathway in a spatially restricted fashion, in our quest for new anti-tumor therapies.

show abstract

Ras oncogenes: split personalities

Cited by 1,319 publications

References 223 publications

Lactate Dehydrogenase B Is Required for the Growth of KRAS-Dependent Lung Adenocarcinomas

Lactate Dehydrogenase B Is Required for the Growth of KRAS-Dependent Lung Adenocarcinomas

Critical role for transcriptional repressor Snail2 in transformation by oncogenic RAS in colorectal carcinoma cells

The Ras‐ERK pathway: Understanding site‐specific signaling provides hope of new anti‐tumor therapies

Contact Info

Product

Resources

About