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Oncogenic KRAS signalling in pancreatic cancer.

Eser S, Schnieke A, Schneider G, Saur D - Br. J. Cancer (2014)

Bottom Line: Rigorous research in the field has uncovered genetic aberrations that occur during PDAC development and progression.This includes context-specific KRAS effector pathways, synthetic lethal interaction partners and KRAS-driven metabolic changes.Here, we review recent advances in oncogenic KRAS signalling and discuss how these might benefit PDAC treatment in the future.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Internal Medicine II, Klinikum rechts der Isar, Technische Universität München, Ismaningerstr. 22, 81675 München, Germany [2] German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.

ABSTRACT
Pancreatic ductal adenocarcinoma (PDAC) is almost universally fatal. The annual number of deaths equals the number of newly diagnosed cases, despite maximal treatment. The overall 5-year survival rate of <5% has remained stubbornly unchanged over the last 30 years, despite tremendous efforts in preclinical and clinical science. There is unquestionably an urgent need to further improve our understanding of pancreatic cancer biology, treatment response and relapse, and to identify novel therapeutic targets. Rigorous research in the field has uncovered genetic aberrations that occur during PDAC development and progression. In most cases, PDAC is initiated by oncogenic mutant KRAS, which has been shown to drive pancreatic neoplasia. However, all attempts to target KRAS directly have failed in the clinic and KRAS is widely assumed to be undruggable. This has led to intense efforts to identify druggable critical downstream targets and nodes orchestrated by mutationally activated KRAS. This includes context-specific KRAS effector pathways, synthetic lethal interaction partners and KRAS-driven metabolic changes. Here, we review recent advances in oncogenic KRAS signalling and discuss how these might benefit PDAC treatment in the future.

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Related in: MedlinePlus

An overview of oncogenic KRAS-driven RAF/MEK/ERK and PI3K/PDK1/AKT signalling networks in pancreatic cancer. Mutationally activated oncogenic KRAS engages the PI3K-PDK1-AKT pathway to drive cancer initiation, progression and maintenance. Additionally, activated KRAS signals through the canonical mitogen-activated protein kinase pathway via RAF-MEK1/2-ERK1/2. KRAS activity is enhanced by positive feedback activation of the epidermal growth factor receptor (EGFR) and possibly by other receptor tyrosine kinases (RTKs) that are engaged by autocrine and paracrine stimuli. Negative feedback loops and inhibitory as well as activating cross-signalling exist at various levels. Activating pro-tumourigenic signalling connections are depicted as arrows in green; inhibitory anti-tumourigenic pathways are shown as solid lines headed by a vertical line in red. Arrows in red depict activating anti-tumourigenic feedback loops. The asterisk (KRAS*) represents the mutational activation of KRAS.
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fig1: An overview of oncogenic KRAS-driven RAF/MEK/ERK and PI3K/PDK1/AKT signalling networks in pancreatic cancer. Mutationally activated oncogenic KRAS engages the PI3K-PDK1-AKT pathway to drive cancer initiation, progression and maintenance. Additionally, activated KRAS signals through the canonical mitogen-activated protein kinase pathway via RAF-MEK1/2-ERK1/2. KRAS activity is enhanced by positive feedback activation of the epidermal growth factor receptor (EGFR) and possibly by other receptor tyrosine kinases (RTKs) that are engaged by autocrine and paracrine stimuli. Negative feedback loops and inhibitory as well as activating cross-signalling exist at various levels. Activating pro-tumourigenic signalling connections are depicted as arrows in green; inhibitory anti-tumourigenic pathways are shown as solid lines headed by a vertical line in red. Arrows in red depict activating anti-tumourigenic feedback loops. The asterisk (KRAS*) represents the mutational activation of KRAS.

Mentions: Oncogenic KRAS signalling is the main driving force behind PDAC. The signalling networks engaged by oncogenic KRAS are highly complex and characterised by the activation of several effector pathways. These are interconnected at various levels by cross-signalling and feedback loops (Figure 1). KRAS-driven signalling networks differ between tumour entities, such as PDAC, NSCLC and colon cancer, and most likely between subtypes of each entity. In different contexts KRAS signalling involves input from different upstream signals and engagement of different downstream effector pathways. Dissection and thorough understanding of these diverse signalling requirements is essential for the development of effective sub-entity-specific targeted strategies. These are urgently needed to improve the poor prognosis for patients suffering from KRAS-driven cancer.


Oncogenic KRAS signalling in pancreatic cancer.

Eser S, Schnieke A, Schneider G, Saur D - Br. J. Cancer (2014)

An overview of oncogenic KRAS-driven RAF/MEK/ERK and PI3K/PDK1/AKT signalling networks in pancreatic cancer. Mutationally activated oncogenic KRAS engages the PI3K-PDK1-AKT pathway to drive cancer initiation, progression and maintenance. Additionally, activated KRAS signals through the canonical mitogen-activated protein kinase pathway via RAF-MEK1/2-ERK1/2. KRAS activity is enhanced by positive feedback activation of the epidermal growth factor receptor (EGFR) and possibly by other receptor tyrosine kinases (RTKs) that are engaged by autocrine and paracrine stimuli. Negative feedback loops and inhibitory as well as activating cross-signalling exist at various levels. Activating pro-tumourigenic signalling connections are depicted as arrows in green; inhibitory anti-tumourigenic pathways are shown as solid lines headed by a vertical line in red. Arrows in red depict activating anti-tumourigenic feedback loops. The asterisk (KRAS*) represents the mutational activation of KRAS.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4150259&req=5

fig1: An overview of oncogenic KRAS-driven RAF/MEK/ERK and PI3K/PDK1/AKT signalling networks in pancreatic cancer. Mutationally activated oncogenic KRAS engages the PI3K-PDK1-AKT pathway to drive cancer initiation, progression and maintenance. Additionally, activated KRAS signals through the canonical mitogen-activated protein kinase pathway via RAF-MEK1/2-ERK1/2. KRAS activity is enhanced by positive feedback activation of the epidermal growth factor receptor (EGFR) and possibly by other receptor tyrosine kinases (RTKs) that are engaged by autocrine and paracrine stimuli. Negative feedback loops and inhibitory as well as activating cross-signalling exist at various levels. Activating pro-tumourigenic signalling connections are depicted as arrows in green; inhibitory anti-tumourigenic pathways are shown as solid lines headed by a vertical line in red. Arrows in red depict activating anti-tumourigenic feedback loops. The asterisk (KRAS*) represents the mutational activation of KRAS.
Mentions: Oncogenic KRAS signalling is the main driving force behind PDAC. The signalling networks engaged by oncogenic KRAS are highly complex and characterised by the activation of several effector pathways. These are interconnected at various levels by cross-signalling and feedback loops (Figure 1). KRAS-driven signalling networks differ between tumour entities, such as PDAC, NSCLC and colon cancer, and most likely between subtypes of each entity. In different contexts KRAS signalling involves input from different upstream signals and engagement of different downstream effector pathways. Dissection and thorough understanding of these diverse signalling requirements is essential for the development of effective sub-entity-specific targeted strategies. These are urgently needed to improve the poor prognosis for patients suffering from KRAS-driven cancer.

Bottom Line: Rigorous research in the field has uncovered genetic aberrations that occur during PDAC development and progression.This includes context-specific KRAS effector pathways, synthetic lethal interaction partners and KRAS-driven metabolic changes.Here, we review recent advances in oncogenic KRAS signalling and discuss how these might benefit PDAC treatment in the future.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Internal Medicine II, Klinikum rechts der Isar, Technische Universität München, Ismaningerstr. 22, 81675 München, Germany [2] German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.

ABSTRACT
Pancreatic ductal adenocarcinoma (PDAC) is almost universally fatal. The annual number of deaths equals the number of newly diagnosed cases, despite maximal treatment. The overall 5-year survival rate of <5% has remained stubbornly unchanged over the last 30 years, despite tremendous efforts in preclinical and clinical science. There is unquestionably an urgent need to further improve our understanding of pancreatic cancer biology, treatment response and relapse, and to identify novel therapeutic targets. Rigorous research in the field has uncovered genetic aberrations that occur during PDAC development and progression. In most cases, PDAC is initiated by oncogenic mutant KRAS, which has been shown to drive pancreatic neoplasia. However, all attempts to target KRAS directly have failed in the clinic and KRAS is widely assumed to be undruggable. This has led to intense efforts to identify druggable critical downstream targets and nodes orchestrated by mutationally activated KRAS. This includes context-specific KRAS effector pathways, synthetic lethal interaction partners and KRAS-driven metabolic changes. Here, we review recent advances in oncogenic KRAS signalling and discuss how these might benefit PDAC treatment in the future.

Show MeSH
Related in: MedlinePlus