A Central Role for RAF→MEK→ERK Signaling in the Genesis of Pancreatic Ductal Adenocarcinoma

Collisson, Eric A.; Trejo, Christy L.; Silva, Jillian M.; Gu, Shenda; Korkola, James E.; Heiser, Laura M.; Charles, Roch‐Philippe; Rabinovich, Brian A.; Hann, Byron; Dankort, David; Spellman, Paul T.; Phillips, Wayne A.; Gray, Joe W.; McMahon, Martin

doi:10.1158/2159-8290.cd-11-0347

Cited by 275 publications

(263 citation statements)

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“…36,37,[49][50][51] We found that at the serum-limiting conditions there was a significantly diminished activation of AKT in KRAS-dependent PDAC as assessed by Ser473 and Thr308-phosphorylation in the absence of HNRNPA2B1 (Fig 4, Fig S8). In contrast, and in agreement with the data above, HNRNPA2B1-depletion had no effect on AKT activation in KRAS-independent PDAC (Fig 4, Fig S8).…”

Section: Induction Of Apoptosis By Hnrnpa2b1 Downregulation In Kras-dmentioning

confidence: 79%

Ribonucleoprotein HNRNPA2B1 Interacts With and Regulates Oncogenic KRAS in Pancreatic Ductal Adenocarcinoma Cells

et al. 2014

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Section: Induction Of Apoptosis By Hnrnpa2b1 Downregulation In Kras-dmentioning

confidence: 79%

Ribonucleoprotein HNRNPA2B1 Interacts With and Regulates Oncogenic KRAS in Pancreatic Ductal Adenocarcinoma Cells

et al. 2014

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“…Moreover, oncogenic BRAF mutations are mutually exclusive with KRAS mutations and are present in >30% of the KRAS wild-type PDAC cases (Witkiewicz et al 2015). Genetic studies in autochthonous models further showed that oncogenic Braf is sufficient to induce PDAC development (Collisson et al 2012), consistent with a strong epistatic relationship between oncogenic BRAF and KRAS mutations in PDAC and implicating the utility of BRAF inhibitors in PDAC. However it should be stressed that any clinical trial with RAF inhibitors should be restricted to patients with confirmed BRAF mutation, since targeting wildtype BRAF with RAF inhibitors can lead to paradoxical activation of ERK signaling through transactivation of CRAF (Poulikakos et al 2010) Together, these observations underscore the complex roles of cellular context in oncogenic KRAS signaling and the need for in-depth genetic analysis of the role and requirement of RAF/MEK/ MAPK pathway components in KRAS-driven PDAC genesis and tumor maintenance.…”

Section: Kras Signaling Surrogates In Tumor Development and Maintenancementioning

confidence: 88%

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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“…The MEK/ERK and the PI3K/mTOR cascade are prototypic survival pathways that have been implicated in tumorogenesis of NRAS mutant melanoma (9,21). Emerging preclinical evidence suggests that combined targeting of these two pathways with selective small-molecule inhibitors might be effective in treating malignancies with preexistent or acquired RAS mutations (22)(23)(24)(25). In this study, we demonstrate that MEKi combined with PI3K/mTOR 1,2 inhibition is able to synergistically reduce cell viability in vitro and decrease tumor size in vivo in a large panel of human NRAS mutant melanoma cells.…”

Section: Discussionmentioning

confidence: 99%

Combined targeting of MEK and PI3K/mTOR effector pathways is necessary to effectively inhibit NRAS mutant melanoma in vitro and in vivo

Posch

Moslehi

Feeney

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Activating mutations in the neuroblastoma rat sarcoma viral oncogene homolog (NRAS) gene are common genetic events in malignant melanoma being found in 15-25% of cases. NRAS is thought to activate both mitogen activated protein kinase (MAPK) and PI3K signaling in melanoma cells. We studied the influence of different components on the MAP/extracellular signal-regulated (ERK) kinase (MEK) and PI3K/mammalian target of rapamycin (mTOR)-signaling cascade in NRAS mutant melanoma cells. In general, these cells were more sensitive to MEK inhibition compared with inhibition in the PI3K/ mTOR cascade. Combined targeting of MEK and PI3K was superior to MEK and mTOR 1,2 inhibition in all NRAS mutant melanoma cell lines tested, suggesting that PI3K signaling is more important for cell survival in NRAS mutant melanoma when MEK is inhibited. However, targeting of PI3K/mTOR 1,2 in combination with MEK inhibitors is necessary to effectively abolish growth of NRAS mutant melanoma cells in vitro and regress xenografted NRAS mutant melanoma. Furthermore, we showed that MEK and PI3K/mTOR 1,2 inhibition is synergistic. Expression analysis confirms that combined MEK and PI3K/mTOR 1,2 inhibition predominantly influences genes in the rat sarcoma (RAS) pathway and growth factor receptor pathways, which signal through MEK/ERK and PI3K/mTOR, respectively. Our results suggest that combined targeting of the MEK/ERK and PI3K/mTOR pathways has antitumor activity and might serve as a therapeutic option in the treatment of NRAS mutant melanoma, for which there are currently no effective therapies.O ncogenic mutations in codons 12, 13, or 61 of the rat sarcoma (RAS) family of small GTPases, Kirsten rat sarcoma viral oncogene homolog (KRAS), Harvey rat sarcoma viral oncogene homolog (HRAS), and neuroblastoma RAS viral oncogene homolog (NRAS) occur in approximately one-third of all human cancers with NRAS mutations found in about 15-20% of melanomas (1-7). Mutated RAS proteins activate signaling pathways that promote the cell division cycle and cell growth and suppress apoptosis. Small interfering RNA (siRNA)-mediated depletion of NRAS in melanoma cell lines inhibits proliferation and renders cells sensitive to chemotherapy, making mutant NRAS and its signaling effectors relevant targets for melanoma therapy (8, 9). Efforts at developing therapeutics that inhibit mutant RAS directly have so far not been successful. The high affinity of RAS for GTP and the high concentrations of GTP intracellularly has meant that the identification of small molecules, which selectively prevent accumulation of RAS-GTP, has not been possible (10). Targeting mutant NRAS with siRNA is still limited to preclinical models because of the significant challenge in delivering antisense oligonucleotides in vivo. The response of NRAS mutant melanoma and other melanomas to various chemotherapeutic regiments has been very scarce with only 6% of patients responding (11). Alternatively, farnesyltransferase inhibitors (FTIs) were thought to inhibit RAS activation by blocking farnesy...

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A Central Role for RAF→MEK→ERK Signaling in the Genesis of Pancreatic Ductal Adenocarcinoma

Cited by 275 publications

References 26 publications

Ribonucleoprotein HNRNPA2B1 Interacts With and Regulates Oncogenic KRAS in Pancreatic Ductal Adenocarcinoma Cells

Ribonucleoprotein HNRNPA2B1 Interacts With and Regulates Oncogenic KRAS in Pancreatic Ductal Adenocarcinoma Cells

Genetics and biology of pancreatic ductal adenocarcinoma

Combined targeting of MEK and PI3K/mTOR effector pathways is necessary to effectively inhibit NRAS mutant melanoma in vitro and in vivo

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