Requirement for Interaction of PI3-Kinase p110α with RAS in Lung Tumor Maintenance

Castellano, Esther; Sheridan, Clare; Thin, May Zaw; Nye, Emma; Spencer‐Dene, Bradley; Diefenbacher, Markus E.; Moore, Christopher; Kumar, Madhu; Murillo, Miguel; Grönroos, Eva; Lassailly, François; Stamp, Gordon; Downward, Julian

doi:10.1016/j.ccr.2013.09.012

Cited by 151 publications

(138 citation statements)

References 34 publications

(45 reference statements)

Supporting

Mentioning

134

Contrasting

Order By: Relevance

“…It has been illustrated that RAS transformed human cells rely on the PI3K pathway to sustain their tumorigenic activity . The requirement for PI3K in tumor maintenance is further supported by a recent GEMM study showing that Kras-driven lung adenocarcinoma growth is halted by the disruption of Pi3k interaction with Ras or inducible p110α deletion in advanced tumors (Castellano et al 2013). Interestingly, in contrast to the rapid tumor regression observed upon Kras extinction in advanced tumors (Collins et al 2012;Ying et al 2012), Pi3k deficiency leads to sustained tumor stasis, and gross tumor regression is only achieved upon cotreatment with a MEK inhibitor, suggesting that both the PI3K and RAF pathways are critical for KRAS-mediated tumor maintenance.…”

Section: Kras Signaling Surrogates In Tumor Development and Maintenancementioning

confidence: 66%

Genetics and biology of pancreatic ductal adenocarcinoma

et al. 2016

View full text Add to dashboard Cite

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...

show abstract

Section: Kras Signaling Surrogates In Tumor Development and Maintenancementioning

confidence: 66%

Genetics and biology of pancreatic ductal adenocarcinoma

et al. 2016

View full text Add to dashboard Cite

show abstract

“…opportunity for inducing tumor cell-autonomous inhibition of tumor growth (6), but the current work extends this to show that this interaction may also be important in host tissue for the building of a favorable niche for tumor growth. The observed effects on tumor-induced angiogenesis were achieved by defective signaling of the VEGF and FGF pathways, anticipating acquired resistance and without any obvious deleterious effect in the long term.…”

Section: Discussionmentioning

confidence: 92%

“…In vivo, the interaction of RAS with PI3K is also needed for proper development of embryonic lymphangiogenesis. Moreover, when the RBD of Pik3ca is mutated in such a way that RAS cannot bind to and activate PI3K, RAS-driven tumor development in the lung and skin is abrogated (5), and preexisting RAS-driven lung tumors undergo partial regression and long-term stasis (6).…”

Section: Introductionmentioning

confidence: 99%

RAS interaction with PI3K p110α is required for tumor-induced angiogenesis

Murillo¹,

Zelenay²,

Nye³

et al. 2014

J. Clin. Invest.

Self Cite

View full text Add to dashboard Cite

“…In an opposing manner, the tumour suppressor Pten inhibits PI3K function by dephosphorylation of its substrate phosphotidyl-inositol 3,4,5 triphosphate 4 . Ras pathway mutation, loss of PTEN and thus constitutive PI3K signalling are frequent in tumours and are hallmarks of lung and pancreatic cancer [2][3][4] . Although PTEN is frequently mutated in tumours, notably, it is not mutated in tumours with Ras mutations, but it is nevertheless repressed in these tumours 3,4 .…”

mentioning

confidence: 99%

“…M utant Ras short circuits growth factor signalling by directly activating PI3K [1][2][3] . In an opposing manner, the tumour suppressor Pten inhibits PI3K function by dephosphorylation of its substrate phosphotidyl-inositol 3,4,5 triphosphate 4 .…”

mentioning

confidence: 99%

Different thresholds of ZEB1 are required for Ras-mediated tumour initiation and metastasis

Liu

Huang

et al. 2014

Nat Commun

View full text Add to dashboard Cite

Ras pathway mutation is frequent in carcinomas where it induces expression of the transcriptional repressor ZEB1. Although ZEB1 is classically linked to epithelial-mesenchymal transition and tumour metastasis, it has an emerging second role in generation of cancerinitiating cells. Here we show that Ras induction of ZEB1 is required for tumour initiation in a lung cancer model, and we link this function to repression Pten, whose loss is critical for emergence of cancer-initiating cells. These two roles for ZEB1 in tumour progression can be distinguished by their requirement for different levels of ZEB1. A lower threshold of ZEB1 is sufficient for cancer initiation, whereas further induction is necessary for tumour metastasis.

show abstract

Requirement for Interaction of PI3-Kinase p110α with RAS in Lung Tumor Maintenance

Cited by 151 publications

References 34 publications

Genetics and biology of pancreatic ductal adenocarcinoma

Genetics and biology of pancreatic ductal adenocarcinoma

RAS interaction with PI3K p110α is required for tumor-induced angiogenesis

Different thresholds of ZEB1 are required for Ras-mediated tumour initiation and metastasis

Contact Info

Product

Resources

About