Abstract
RAS family proteins are important signaling molecules that regulate cell growth, survival and differentiation by coupling receptor activation to downstream effector pathways. Three distinct genes encode for the three different proteins H-, K-, and N- RAS. These proteins share high sequence homology, particularly at the N-Terminal domain. Among them, K-RAS is one of the most frequently mutated in human cancer. The majority of the mutations present in K-RAS are at codon 12 (from 80 to 100%) followed by codon 13 and 61. In all cases, aminoacid change leads to a constitutively activated protein.
K-RAS mutations have a role in tumor development as well as in tumor progression and resistance. Despite the various studies which have been published, the prognostic and predictive role of K-RAS mutations is still under debate. Keeping in mind that the glycine present at position 12 can be substituted by valine, aspartic acid or cysteine, it could be well understood that each different substitution plays a different role in K-RAS-dependent processes.
The present article focuses on the molecular and biological characteristics of K-RAS protein, its role in NSCLC tumor development and progression. We also present an overview of the preclinical models both in vitro and in vivo available to determine the role of K-RAS in tumor progression and response to treatment and on the recent results obtained in this field. Finally, we have considered the impact of KRAS mutations in clinical practice, analyzing the different recent trials that have taken into consideration K-RAS.
Keywords: K-RAS, non-small-cell-lung cancer, mutation, animal model, synthetic lethality, cell response, prognosis.
Current Pharmaceutical Design
Title:Across the Universe of K-Ras Mutations in Non-Small-Cell-Lung Cancer
Volume: 20 Issue: 24
Author(s): Sheila Piva, Monica Ganzinelli, Marina Chiara Garassino, Elisa Caiola, Gabriella Farina, Massimo Broggini and Mirko Marabese
Affiliation:
Keywords: K-RAS, non-small-cell-lung cancer, mutation, animal model, synthetic lethality, cell response, prognosis.
Abstract: RAS family proteins are important signaling molecules that regulate cell growth, survival and differentiation by coupling receptor activation to downstream effector pathways. Three distinct genes encode for the three different proteins H-, K-, and N- RAS. These proteins share high sequence homology, particularly at the N-Terminal domain. Among them, K-RAS is one of the most frequently mutated in human cancer. The majority of the mutations present in K-RAS are at codon 12 (from 80 to 100%) followed by codon 13 and 61. In all cases, aminoacid change leads to a constitutively activated protein.
K-RAS mutations have a role in tumor development as well as in tumor progression and resistance. Despite the various studies which have been published, the prognostic and predictive role of K-RAS mutations is still under debate. Keeping in mind that the glycine present at position 12 can be substituted by valine, aspartic acid or cysteine, it could be well understood that each different substitution plays a different role in K-RAS-dependent processes.
The present article focuses on the molecular and biological characteristics of K-RAS protein, its role in NSCLC tumor development and progression. We also present an overview of the preclinical models both in vitro and in vivo available to determine the role of K-RAS in tumor progression and response to treatment and on the recent results obtained in this field. Finally, we have considered the impact of KRAS mutations in clinical practice, analyzing the different recent trials that have taken into consideration K-RAS.
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Cite this article as:
Piva Sheila, Ganzinelli Monica, Garassino Chiara Marina, Caiola Elisa, Farina Gabriella, Broggini Massimo and Marabese Mirko, Across the Universe of K-Ras Mutations in Non-Small-Cell-Lung Cancer, Current Pharmaceutical Design 2014; 20 (24) . https://dx.doi.org/10.2174/13816128113196660761
DOI https://dx.doi.org/10.2174/13816128113196660761 |
Print ISSN 1381-6128 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4286 |
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