Variation in KRAS driver substitution distributions between tumor types is determined by both mutation and natural selection

Ostrow, Sheli L.; Simon, Einav; Prinz, Elad; Bick, Tova; Shentzer, Talia; Nagawkar, Sima S.; Sabo, Edmond; Ben‐Izhak, Ofer; Hershberg, Ruth; Hershkovitz, Dov

doi:10.1038/srep21927

Cited by 11 publications

(7 citation statements)

References 53 publications

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“…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).…”

Section: Discussionmentioning

confidence: 99%

KRAS Alleles: The Devil Is in the Detail

2017

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KRAS is the most frequently mutated oncogene in cancer and KRAS mutation is commonly associated with poor prognosis and resistance to therapy. Since the KRAS oncoprotein is, as yet, not directly druggable, efforts to target KRAS mutant cancers focus on identifying vulnerabilities in downstream signaling pathway or in stress-response pathways that are permissive for strong oncogenic signaling. One aspect of KRAS biology that is not well appreciated is the potential biological differences between the many distinct KRAS activating mutations. This review draws upon insights from both clinical and experimental studies to explore similarities and differences among KRAS alleles. Historical and emerging evidence supports the notion that the specific biology related to each allele might be exploitable for allele-specific therapy.

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Section: Discussionmentioning

confidence: 99%

KRAS Alleles: The Devil Is in the Detail

2017

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“…A notable example is provided by the difficulty in explaining the distribution of mutations that often occurs within signalling pathways that drive carcinogenesis in different tissues [ 45 , 46 , 47 ]. Even a given oncogenic driver ( e.g., KRAS) can exhibit distinct mutational patterns or gene amplifications that remain difficult to explain by tissue-dependent mutagenesis [ 48 , 49 ]. We can hypothesise that mutations result both in quantitative and qualitative alterations of cell signalling.…”

Section: Homeostasis Heterogeneity and Diseasementioning

confidence: 99%

Signalling dynamics, cell decisions, and homeostatic control in health and disease

Valls

Esposito

2022

Current Opinion in Cell Biology

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“…The most common causes of hereditary pancreatitis involve germline mutations in PRSS1, encoding trypsinogen, or SPINK1, a serine protease inhibitor that limits trypsin activity, suggesting that chronic exposure of the pancreas to its own damaging projects may be a major etiologic factor in pancreatic carcinogenesis [18]. In contrast to KRAS G12C transversion mutations, which are associated with smoking and commonly found in LUAC, PDAC is commonly associated with KRAS G12D or KRAS G12V , revealing mutational predilection or selection for these particular amino acid changes [19]. …”

Section: Kras Signaling and Inflammation In Pancreatic Ductal Carcmentioning

confidence: 99%

Inflammation as a driver and vulnerability of KRAS mediated oncogenesis

Kitajima

Thummalapalli

Barbie

2016

Seminars in Cell & Developmental Biology

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While important strides have been made in cancer therapy by targeting certain oncogenes, KRAS, the most common among them, remains refractory to this approach. In recent years, a deeper understanding of the critical importance of inflammation in promoting KRAS-driven oncogenesis has emerged, and applies across the different contexts of lung, pancreatic, and colorectal tumorigenesis. Here we review why these tissue types are particularly prone to developing KRAS mutations, and how inflammation conspires with KRAS signaling to fuel carcinogenesis. We discuss multiple lines of evidence that have established NF-κB, STAT3, and certain cytokines as key transducers of these signals, and data to suggest that targeting these pathways has significant clinical potential. Furthermore, recent work has begun to uncover how inflammatory signaling interacts with other KRAS regulated survival pathways such as autophagy and MAPK signaling, and that co-targeting these multiple nodes may be required to achieve real benefit. In addition, the impact of KRAS associated inflammatory signaling on the greater tumor microenvironment has also become apparent, and taking advantage of this inflammation by incorporating approaches that harness T cell anti-tumor responses represents another promising therapeutic strategy. Finally, we highlight the likelihood that the genomic complexity of KRAS mutant tumors will ultimately require tailored application of these therapeutic approaches, and that targeting inflammation early in the course of tumor development could have the greatest impact on eradicating this deadly disease.

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Variation in KRAS driver substitution distributions between tumor types is determined by both mutation and natural selection

Cited by 11 publications

References 53 publications

KRAS Alleles: The Devil Is in the Detail

KRAS Alleles: The Devil Is in the Detail

Signalling dynamics, cell decisions, and homeostatic control in health and disease

Inflammation as a driver and vulnerability of KRAS mediated oncogenesis

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