PI3K Regulation of RAC1 Is Required for KRAS-Induced Pancreatic Tumorigenesis in Mice

Wu, Chia Yen C.; Carpenter, Eileen S.; Takeuchi, Kenneth K.; Halbrook, Christopher J.; Peverley, Louise V.; Bien, Harold; Hall, Jason C.; DelGiorno, Kathleen E.; Pal, Debjani; Song, Yan; Shi, Chanjuan; Lin, Richard Z.; Crawford, Howard C.

doi:10.1053/j.gastro.2014.08.032

Cited by 110 publications

(104 citation statements)

References 39 publications

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“…Pik3ca ablation and chronic inhibition led to up-regulation of AKT signaling, possibly resulting from compensatory activity from other PI3K isoforms. In contrast, Pik3ca ablation significantly diminished both Rac1 activity and expression in Kras mutant pancreatic cells, accompanied by significant inhibition of Kras-activated Rac1 guanine exchange factors Tiam1 and Vav1 [69]. Pancreas-specific ablation of Rac1 has the same phenotype as Pik3ca ablation in Kras mutant mice [68,69], indicating the PI3K/RAC axis plays an important role in Kras-driven pancreatic tumor development.…”

Section: Expression Of Mutant Krasmentioning

confidence: 94%

“…In contrast, Pik3ca ablation significantly diminished both Rac1 activity and expression in Kras mutant pancreatic cells, accompanied by significant inhibition of Kras-activated Rac1 guanine exchange factors Tiam1 and Vav1 [69]. Pancreas-specific ablation of Rac1 has the same phenotype as Pik3ca ablation in Kras mutant mice [68,69], indicating the PI3K/RAC axis plays an important role in Kras-driven pancreatic tumor development. Similarly, Stat3 phosphorylation is found to occur at multiple stages of Kras 12D -driven pancreatic tumorigenesis but not in normal pancreatic tissue [76,77].…”

Section: Expression Of Mutant Krasmentioning

confidence: 94%

“…Pancreas-specific inactivation of Pik3ca, but not Pik3cb, prevented the occurrence of all types of malignant lesions induced by expression of mutant Kras, including PanIN and acinar-to-ductal metaplasia [69,85]. Pik3ca ablation and chronic inhibition led to up-regulation of AKT signaling, possibly resulting from compensatory activity from other PI3K isoforms.…”

Section: Expression Of Mutant Krasmentioning

confidence: 96%

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RAS signaling and anti-RAS therapy: lessons learned from genetically engineered mouse models, human cancer cells, and patient-related studies

Fang¹

2016

ABBS

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Activating mutations of oncogenic RAS genes are frequently detected in human cancers. The studies in genetically engineered mouse models (GEMMs) reveal that Kras-activating mutations predispose mice to early onset tumors in the lung, pancreas, and gastrointestinal tract. Nevertheless, most of these tumors do not have metastatic phenotypes. Metastasis occurs when tumors acquire additional genetic changes in other cancer driver genes. Studies on clinical specimens also demonstrated that KRAS mutations are present in premalignant tissues and that most of KRAS mutant human cancers have co-mutations in other cancer driver genes, including TP53, STK11, CDKN2A, and KMT2C in lung cancer; APC, TP53, and PIK3CA in colon cancer; and TP53, CDKN2A, SMAD4, and MED12 in pancreatic cancer. Extensive efforts have been devoted to develop therapeutic agents that target enzymes involved in RAS posttranslational modifications, that inhibit downstream effectors of RAS signaling pathways, and that kill RAS mutant cancer cells through synthetic lethality. Recent clinical studies have revealed that sorafenib, a pan-RAF and VEGFR inhibitor, has impressive benefits for KRAS mutant lung cancer patients. Combination therapy of MEK inhibitors with either docetaxel, AKT inhibitors, or PI3K inhibitors also led to improved clinical responses in some KRAS mutant cancer patients. This review discusses knowledge gained from GEMMs, human cancer cells, and patient-related studies on RAS-mediated tumorigenesis and anti-RAS therapy. Emerging evidence demonstrates that RAS mutant cancers are heterogeneous because of the presence of different mutant alleles and/or co-mutations in other cancer driver genes. Effective subclassifications of RAS mutant cancers may be necessary to improve patients' outcomes through personalized precision medicine.

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Section: Expression Of Mutant Krasmentioning

confidence: 94%

Section: Expression Of Mutant Krasmentioning

confidence: 94%

Section: Expression Of Mutant Krasmentioning

confidence: 96%

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RAS signaling and anti-RAS therapy: lessons learned from genetically engineered mouse models, human cancer cells, and patient-related studies

Fang¹

2016

ABBS

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“…In the PI3K pathway, studies have consistently shown that, among the major kinase subunits of PI3K, p110α, but not p110β, is the major oncogenic KRAS effector to activate PI3K and promote tumor growth of PDAC and multiple other cancer types (Gupta et al 2007;Baer et al 2014;Gritsman et al 2014;Wu et al 2014). The essential role of the PI3K pathway is supported by additional genetic studies showing that oncogenic Kras-driven PDAC development is abolished upon deletion of Pdk1, the central downstream kinase mediating PI3K signaling (Eser et al 2013).…”

Section: Kras Signaling Surrogates In Tumor Development and Maintenancementioning

confidence: 99%

Genetics and biology of pancreatic ductal adenocarcinoma

et al. 2016

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With 5-year survival rates remaining constant at 6% and rising incidences associated with an epidemic in obesity and metabolic syndrome, pancreatic ductal adenocarcinoma (PDAC) is on track to become the second most common cause of cancer-related deaths by 2030. The high mortality rate of PDAC stems primarily from the lack of early diagnosis and ineffective treatment for advanced tumors. During the past decade, the comprehensive atlas of genomic alterations, the prominence of specific pathways, the preclinical validation of such emerging targets, sophisticated preclinical model systems, and the molecular classification of PDAC into specific disease subtypes have all converged to illuminate drug discovery programs with clearer clinical path hypotheses. A deeper understanding of cancer cell biology, particularly altered cancer cell metabolism and impaired DNA repair processes, is providing novel therapeutic strategies that show strong preclinical activity. Elucidation of tumor biology principles, most notably a deeper understanding of the complexity of immune regulation in the tumor microenvironment, has provided an exciting framework to reawaken the immune system to attack PDAC cancer cells. While the long road of translation lies ahead, the path to meaningful clinical progress has never been clearer to improve PDAC patient survival. Pancreatic ductal adenocarcinoma (PDAC) pathogenesisOn gross inspection, PDAC presents as a poorly demarcated, firm white-yellow mass, with the surrounding nonmalignant pancreas typically showing atrophy, fibrosis, and dilated ducts due to the obstructive effects of expanding carcinoma. Microscopically, these neoplasms vary from well-differentiated gland-forming carcinomas to poorly differentiated "sarcomatoid" carcinomas diagnosed only upon immunolabeling due to predominant mesenchymal features (Hruban et al. 2007). PDAC evolves from well-defined precursor lesions that, in the context of their genetic features, define the genetic progression model of pancreatic carcinogenesis (Yachida et al. 2010). Early disease histology manifests as several distinct types of precursor lesions-the most common are microscopic pancreatic intraepithelial neoplasia (PanIN), followed by the macroscopic cysts; namely, the intraductal papillary mucinous neoplasm (IPMN) and mucinous cystic neoplasm (MCN) (Matthaei et al. 2011). Since most PDAC cases become clinically apparent at advanced stages, major opportunities to reduce mortality rest with diagnostics and treatments that would enable the reliable identification and elimination of high-risk precursor lesions. Thus, the identification of these precursor lesions has provided an essential framework to define the genomic features that drive progression to advanced disease and develop effective screening and targeted therapeutics for earlier stage disease (Eser et al. 2011).The noninvasive PanIN lesions were formerly classified into three grades according to the extent of cytological and architectural atypia: PanIN1A (flat lesion) and PanIN1B (micropapillary...

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“…One can therefore ask the question of the use of targeted therapies in this context, including those targeting the PI3K/AKT pathway [2]. Indeed, the lipid kinase PI3Kα was shown to drive pancreatic cancer initiation downstream the main driving oncogene of this cancer [3][4][5][6], oncogenic Kras, found mutated in more than 80% of all pancreatic cancer patients.…”

Section: Introductionmentioning

confidence: 99%

Opportunities and Resistance to Signal-Targeted Therapies in Pancreatic Cancer: What Can we Learn from Proteomic Studies?

Cintas¹,

Douché²,

Guillermet-Guibert³

2018

Preprint

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In metastatic pancreatic cancer patients non eligible to surgery, signal-targeted therapies so far failed to show a significant amelioration of survival. These therapeutic options were tested in Phase II/III clinical trials mostly in combination with the reference treatment Gemcitabine. These innovative therapies aim at annihilating the oncogene dependency; they also aim at renormalizing the tumoral stroma to allow immune cell function or re-vascularisation. Transcriptomics and genomics large scale analysis show the great heterogeneity of pancreatic cancers and failed to clearly delineate specific oncogene dependency besides oncogenic Kras. In this review, we will describe the most recent proteomic data in pancreatic tumors and its metastasis, which could help at identifying their major signalling dependencies, as well as explain why they are intrinsically resistant to signal-targeted therapies. We will also discuss why PI3K signalling, as a paradigm of pro-tumorigenic cell signalling and of tumoral adaptative resistance to drugs, is a relevant target in this context. Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted:

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PI3K Regulation of RAC1 Is Required for KRAS-Induced Pancreatic Tumorigenesis in Mice

Cited by 110 publications

References 39 publications

RAS signaling and anti-RAS therapy: lessons learned from genetically engineered mouse models, human cancer cells, and patient-related studies

RAS signaling and anti-RAS therapy: lessons learned from genetically engineered mouse models, human cancer cells, and patient-related studies

Genetics and biology of pancreatic ductal adenocarcinoma

Opportunities and Resistance to Signal-Targeted Therapies in Pancreatic Cancer: What Can we Learn from Proteomic Studies?

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