Trends in Cancer
ReviewKRAS Alleles: The Devil Is in the Detail
Section snippets
KRAS Is an Oncogenic GTPase
The RAS oncogene family is comprised of three members (KRAS, HRAS, and NRAS) that play an important role in human cancer [1]. All RAS genes encode 21-kDa monomeric GTPases that function to transduce extracellular signals to intracellular signal transduction cascades. The on/off state of rat sarcoma (RAS) proteins is determined by nucleotide binding, with the GTP-bound form existing in an active signaling conformation. Missense mutations in RAS proteins alter the homeostatic balance of GDP and
KRAS Allelic Variation
As the sequences of whole cancer genomes become available, we are getting an unparalleled look at the frequency and variability of KRAS alleles across the spectrum of primary and metastatic cancers (Figure 1A,B) [3]. Among the cancers in which KRAS mutations are most common – pancreatic ductal adenocarcinoma (PDAC), colorectal cancer (CRC), and non-small cell lung cancer (NSCLC) – codon 12 mutations predominate, accounting for nearly 90% of all KRAS mutations (Figure 1C). The likelihood of
Biochemistry of KRAS Alleles
Even before mutations in c-RAS genes were found in human cancers, much of our fundamental knowledge about the biochemistry and cell biology of oncogenic forms of RAS proteins had been established. That RAS proteins bind GTP [11], are associated with the plasma membrane [12], and are prenylated [13] was established through studies of viral RAS (v-RAS). Comparisons between v-RAS and c-RAS – which differ at codons 12 and 59 – revealed that v-RAS exhibits autokinase activity and has reduced GTPase
Epidemiology of KRAS Alleles
One question that arises from somatic genetic analysis is whether KRAS allele choice influences the clinical aspects of a given cancer. The prognostic value of KRAS mutations has been studied extensive in many different cancer contexts and in some of these studies the role of different alleles has been examined. For example, in PDAC, G12D mutation, the most common allele, is associated with a lower probability of survival, while patients with G12R mutation fare better [23] (Figure 2A). In CRC,
KRAS Mutational Status as a Predictive Factor
Chemotherapy remains the first-line treatment for most cancers. In patients with advanced CRC who are treated with folinic acid, fluorouracil, and oxaliplatin (FOLFOX), the standard first-line therapy for CRC, KRAS mutation is predictive of inferior response and this overall effect is driven largely by those cancers expressing G12D [35]. Consistent with the observation that patients with G12V mutations do better than those with other codon 12 mutations in terms of overall survival [27],
Ectopic Expression of KRAS Alleles in Experimental Systems
While studies of human cancer patients are not yet able to provide a definitive link between KRAS and its unique alleles with particular clinical behaviors, they provide statistical correlations that are useful for generating experimentally testable hypotheses. Those working in the RAS field were keen on the concept of allelic variation early on, although at that time, because isoform-specific functions were not as well appreciated, most studies focused on HRAS. For example, in cells
Endogenous Mutant KRAS Alleles in Experimental Systems
One approach for studying the biology of endogenous alleles is to compare primary human cancers or human cancer cell lines with different KRAS mutations. For example, in a gene expression analysis of primary NSCLCs, those expressing G12C or G12V have distinct gene expression profiles relative to cell lines expressing other alleles [38]. The problem with these types of studies is that it is impossible to separate any given KRAS allele from the genetic background with which it is associated. This
Translating KRAS Biochemistry into Cellular Phenotypes
It is likely that the core biochemical properties (hydrolysis and exchange) of mutant KRAS proteins only partially account for their oncogenic activities. Mutant forms of KRAS differ from WT and from other mutants, for example, in their affinity for RAF and other effectors 16, 64. Although no single biochemical quality of the different alleles predicts KRAS allele frequency, a metric that accounts for GTPase activity and effector binding, a biochemical activation score, can predict allele
Prospects for Allele-Specific Therapies
The ultimate goal of studying individual KRAS mutations is to identify allele-specific therapeutic strategies. Thus far, this has only been achieved for G12C, for which inhibitors have been developed that can covalently bind to the cysteine and inhibit the activated oncoprotein 65, 66. One such inhibitor (ARS853) interacts selectively with GDP-bound KRAS and prevents the nucleotide exchange that is required for full activation of codon 12 alleles [67]. This is the same mechanism proposed for
Concluding Remarks
There is compelling evidence that passive mutational mechanisms and active biological selection drive allele choice in cancer [70]. For example, smoking-related mutation patterns clearly drive codon 12 allele selection in lung cancer (Figure 1D). In contrast, biochemical properties of different KRAS alleles likely contribute to allele selection over a broad spectrum of cancer types (Figure 3E). Other aspects of allele selection are less well characterized (see Outstanding Questions), for
Acknowledgments
I apologize to authors whose work was not cited due to space limitations, in particular those individuals who performed detailed early work on the biochemistry and structural biology of RAS proteins. A special thank you to Louis Buscail, Robert Jones, Pierre Laurent-Puig, Julien Taieb and Karine Le Malicot for sharing the clinical data that were used to create the curves in Figure 2 and to Julien Sage for helpful comments on the manuscript. Christian Johnson generated the KRAS structure in
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