Development of siRNA Payloads to Target <i>KRAS</i>-Mutant Cancer

Yuan, Tina L.; Fellmann, Christof; Lee, Chih-Shia; Ritchie, Cayde; Thapar, Vishal; Lee, Liam C.; Hsu, Dennis J.; Grace, Danielle; Carver, Joseph O.; Zuber, Johannes; Luo, Ji; McCormick, Frank; Lowe, Scott W.

doi:10.1158/2159-8290.cd-13-0900

Cited by 97 publications

(101 citation statements)

References 38 publications

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“…RAF or PI3K effectors) (Fruman and Rommel, 2014;Samatar and Poulikakos, 2014), (iv) inhibitors of processes that support the increased metabolic needs of cancer cells (e.g. macropinocytosis, autophagy, glucose and glutamine metabolism), (v) unbiased genetic or chemical screens for synthetic lethal interactors Kumar et al, 2012;Luo et al, 2009;Sarthy et al, 2007;Scholl et al, 2009) and (vi) RNA interference (RNAi) of KRAS expression (Pecot et al, 2014;Xue et al, 2014;Yuan et al, 2014).…”

Section: Box 2 Approaches For Targeting Rasmentioning

confidence: 99%

RAS isoforms and mutations in cancer at a glance

Hobbs

Der

Rossman

2016

Journal of Cell Science

779

709

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RAS proteins (KRAS4A, KRAS4B, NRAS and HRAS) function as GDP-GTP-regulated binary on-off switches, which regulate cytoplasmic signaling networks that control diverse normal cellular processes. Gain-of-function missense mutations in RAS genes are found in ∼25% of human cancers, prompting interest in identifying anti-RAS therapeutic strategies for cancer treatment. However, despite more than three decades of intense effort, no anti-RAS therapies have reached clinical application. Contributing to this failure has been an underestimation of the complexities of RAS. First, there is now appreciation that the four human RAS proteins are not functionally identical. Second, with >130 different missense mutations found in cancer, there is an emerging view that there are mutation-specific consequences on RAS structure, biochemistry and biology, and mutation-selective therapeutic strategies are needed. In this Cell Science at a Glance article and accompanying poster, we provide a snapshot of the differences between RAS isoforms and mutations, as well as the current status of anti-RAS drug-discovery efforts.

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Section: Box 2 Approaches For Targeting Rasmentioning

confidence: 99%

RAS isoforms and mutations in cancer at a glance

Hobbs

Der

Rossman

2016

Journal of Cell Science

779

709

View full text Add to dashboard Cite

show abstract

“…Direct RAS targeting is also using "structure-activity relationships (SARs) by NMR" strategies that search for molecules binding to several weak pockets that can then be bridged together as a means of strengthening interactions and improving specificity (Shuker et al 1996;Sun et al 2014). Beyond this specific program, other more general oncogenic RAS targeting strategies directly inhibit oncogenic KRAS expression with siRNA nanoparticles, which have shown positive results in xenograft models (Zorde Khvalevsky et al 2013;Yuan et al 2014). Current in vivo siRNA delivery methods remain inadequate to target cancer cells (Williford et al 2014), although exosome-based delivery particles may offer improved pharmacology (Wahlgren et al 2012).…”

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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“…Additionally, the G12S mutation induces resistance to all drugs targeting upstream of any pathway in which KRAS is involved (i.e., gefitinib) (7). Several attempts to target KRAS-mutant cancers have used small noncoding RNA (sncRNA), in particular, small-interfering RNA (siRNA) targeting KRAS pathways (8). Given the intrinsic limitations of siRNA targeting, there are not effective siRNAbased strategies to specifically target KRAS mutations without affecting KRAS WT (9), and such indiscriminate targeting is likely to be toxic (10)(11)(12).…”

mentioning

confidence: 99%

Selective targeting of point-mutated KRAS through artificial microRNAs

Acunzo

Romano

Nigita

et al. 2017

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

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Mutated protein-coding genes drive the molecular pathogenesis of many diseases, including cancer. Specifically, mutated KRAS is a documented driver for malignant transformation, occurring early during the pathogenesis of cancers such as lung and pancreatic adenocarcinomas. Therapeutically, the indiscriminate targeting of wild-type and point-mutated transcripts represents an important limitation. Here, we leveraged on the design of miRNA-like artificial molecules (amiRNAs) to specifically target point-mutated genes, such as KRAS, without affecting their wild-type counterparts. Compared with an siRNA-like approach, the requirement of perfect complementarity of the microRNA seed region to a given target sequence in the microRNA/target model has proven to be a more efficient strategy, accomplishing the selective targeting of point-mutated KRAS in vitro and in vivo

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Development of siRNA Payloads to Target KRAS-Mutant Cancer

Cited by 97 publications

References 38 publications

RAS isoforms and mutations in cancer at a glance

RAS isoforms and mutations in cancer at a glance

Genetics and biology of pancreatic ductal adenocarcinoma

Selective targeting of point-mutated KRAS through artificial microRNAs

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