Targeting RAS Membrane Association: Back to the Future for Anti-RAS Drug Discovery?

Cox, Adrienne D.; Der, Channing J.; Philips, Mark R.

doi:10.1158/1078-0432.ccr-14-3214

Cited by 320 publications

(299 citation statements)

References 98 publications

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“…FTase has been recently suggested as a drug target in the development of anti-cancer therapy (7,9). In the present study, it was demonstrated that FTI-277 exerted a more potent anti-proliferative effect on breast cells expressing an active mutant of H-Ras (H-Ras-MCF10A and Hs578T cells) than breast cells expressing wild-type H-Ras (MDA-MB-231 cells).…”

Section: Discussionmentioning

confidence: 57%

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Farnesyl transferase inhibitor FTI-277 inhibits breast cell invasion and migration by blocking H-Ras activation

2016

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Abstract. Hyperactive Ras promotes proliferation and malignant phenotypic conversion of cells in cancer. Ras protein must be associated with cellular membranes for its oncogenic activities through post-translational modifications, including farnesylation. Farnesyltransferase (FTase) is essential for H-Ras membrane targeting, and H-Ras, but not N-Ras, has been demonstrated to cause an invasive phenotype in MCF10A breast epithelial cells. In the present study, it was observed that an FTase inhibitor (FTI), FTI-277, blocked epidermal growth factor (EGF)-induced H-Ras activation, but not N-Ras activation in MDA-MB-231 cells, which express wild-type H-Ras and N-Ras. FTI-277 exerted a more potent inhibitory effect on the proliferation of H-Ras-MCF10A cells and Hs578T breast cancer cells expressing an active mutant of H-Ras than that of MDA-MB-231 cells. The invasive/migratory phenotypes of the H-Ras-MCF10A and Hs578T cells were effectively inhibited by FTI-277 treatment. By contrast, FTI-277 did not affect the invasive/migratory phenotypes of MDA-MB-231 cells. However, the EGF-induced invasion of MDA-MB-231 cells was decreased by FTI-277, implicating that FTI-277 inhibits breast cell invasion and migration by blocking H-Ras activation. Taken together, the results of the present study suggest that FTase inhibition by FTI-277 may be an effective strategy for targeting H-Ras-mediated proliferation, migration and invasion of breast cells.

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Section: Discussionmentioning

confidence: 57%

“…Farnesylation by FTase is the first irreversible, rate-limiting step for Ras membrane association and an obligate modification for oncogenic Ras biological activity (7). Initial attempts to inhibit FTase have been made in the development of anti-cancer agents (2,8,9).…”

Section: Introductionmentioning

confidence: 99%

Farnesyl transferase inhibitor FTI-277 inhibits breast cell invasion and migration by blocking H-Ras activation

2016

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“…The Kras gene encodes the protein of p21 RAS, which is a small GTPase that acts as a molecular switch by coupling cell membrane growth signals to intracellular signaling pathways and transcription factors to control multiple cellular processes (25,26). Oncogenically mutated RAS proteins fail to cycle "off" from the active, GTP-bound state to the inactive GDP-bound state, and thereby accumulated in the constitutive "on" configuration (27). Kras is the most common oncogene that has been found to be mutated in pancreatic cancer.…”

Section: Discussionmentioning

confidence: 99%

Oncogenic KRAS Targets MUC16/CA125 in Pancreatic Ductal Adenocarcinoma

Liang

Qin

Zhang

et al. 2017

Molecular Cancer Research

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“…In the case of KRAS, this attachment requires the post-translational lipid modification of farnesylation (Cox et al 2015). While early efforts to target KRAS farnesylation have failed therapeutically, new small molecule inhibitors have been developed that instead target PDEδ, which binds to farnesylated KRAS and enhances its localization to plasma membranes (Chandra et al 2012;Zimmermann et al 2013).…”

Section: Targeting the Kras Pathwaymentioning

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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Targeting RAS Membrane Association: Back to the Future for Anti-RAS Drug Discovery?

Cited by 320 publications

References 98 publications

Farnesyl transferase inhibitor FTI-277 inhibits breast cell invasion and migration by blocking H-Ras activation

Farnesyl transferase inhibitor FTI-277 inhibits breast cell invasion and migration by blocking H-Ras activation

Oncogenic KRAS Targets MUC16/CA125 in Pancreatic Ductal Adenocarcinoma

Genetics and biology of pancreatic ductal adenocarcinoma

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