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Development of siRNA Payloads to Target KRAS -Mutant Cancer
Open accessPublished version of a preprint
Abstract
UNLABELLED: RNAi is a powerful tool for target identification and can lead to novel therapies for pharmacologically intractable targets such as KRAS. RNAi therapy must combine potent siRNA payloads with reliable in vivo delivery for efficient target inhibition. We used a functional "Sensor" assay to establish a library of potent siRNAs against RAS pathway genes and to show that they efficiently suppress their targets at low dose. This reduces off-target effects and enables combination gene knockdown. We administered Sensor siRNAs in vitro and in vivo and validated the delivery of KRAS siRNA alone and siRNA targeting the complete RAF effector node (A/B/CRAF) as promising strategies to treat KRAS-mutant colorectal cancer. We further demonstrate that improved therapeutic efficacy is achieved by formulating siRNA payloads that combine both single-gene siRNA and node-targeted siRNAs (KRAS + PIK3CA/B). The customizable nature of Sensor siRNA payloads offers a universal platform for the combination target identification and development of RNAi therapeutics. SIGNIFICANCE: To advance RNAi therapy for KRAS-mutant cancer, we developed a validated siRNA library against RAS pathway genes that enables combination gene silencing. Using an in vivo model for real-time siRNA delivery tracking, we show that siRNA-mediated inhibition of KRAS as well as RAF or PI3K combinations can impair KRAS-mutant colorectal cancer in xenograft models.
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“Each siRNA is then processed by the endogenous RNA-induced silencing complex prior to binding to the target RNA, in this case, KRAS, thereby inhibiting translation and promoting mRNA degradation [66,67,68].”
From KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance (2024) · cites this paper as [67]
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Cites
Bartel (2004) · doi:10.1016/s0092-8674(04)00045-5 · Cited by 34,714
Hannon, G. J. (2002) · Nature · doi:10.1038/418244a · Cited by 3,651
Hopkins, A. L., & Groom, C. R. (2002) · Nature Reviews Drug Discovery · doi:10.1038/nrd892 · Cited by 3,305 · cited 1×
“RNAi can, in principle, be applied to reversibly silence any target gene [reviewed in (8, 9)], thereby increasing the druggable landscape from 10% to virtually 100% of the genome (10, 11).”
BackgroundEvidence of RNAi in humans from systemically administered siRNA via targeted nanoparticles
Davis, M. E., Zuckerman, J. E., Choi, C. H. J., Seligson, D. B., Tolcher, A. W., Alabi, C. A., Yen, Y., Heidel, J. D., & Ribas, A. (2010) · Nature · doi:10.1038/nature08956 · Cited by 2,541 · cited 2×
“Sensor siRNAs can be effectively delivered in vivo To test the therapeutic efficacy of Sensor siRNAs in vivo, we used previously characterized cyclodextrin-polymer nanoparticles (29, 30) to deliver Sensor siRNAs to tumors in mice.”
BackgroundMethodExpression profiling reveals off-target gene regulation by RNAi
Jackson, A. L., Bartz, S. R., Schelter, J., Kobayashi, S. V., Burchard, J., Mao, M., Li, B., Cavet, G., & Linsley, P. S. (2003) · Nature Biotechnology · doi:10.1038/nbt831 · Cited by 2,370
RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF
Poulikakos, P. I., Zhang, C., Bollag, G. E., Shokat, K. M., & Rosen, N. X. (2010) · Nature · doi:10.1038/nature08902 · Cited by 1,841 · cited 2×
“In comparison, the small molecule BRAF inhibitor PLX4720 did not inhibit the proliferation of KRAS-mutant cells (Figure 4B), as previously reported (2, 3, 26).”
BackgroundResultRAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth
Hatzivassiliou, G., Song, K. W., Yen, I., Brandhuber, B. J., Anderson, D. J., Alvarado, R., Ludlam, M. J. C., Stokoe, D., Gloor, S. L., Vigers, G. P. A., et al. (2010) · Nature · doi:10.1038/nature08833 · Cited by 1,649 · cited 2×
“In comparison, the small molecule BRAF inhibitor PLX4720 did not inhibit the proliferation of KRAS-mutant cells (Figure 4B), as previously reported (2, 3, 26).”
BackgroundResultKinase-Dead BRAF and Oncogenic RAS Cooperate to Drive Tumor Progression through CRAF
Heidorn, S. J., Milagre, C. S., Whittaker, S. R., Nourry, A., Niculescu‐Duvaz, I., Dhomen, N. S., Hussain, J., Reis-Filho, J. S., Springer, C. J., Pritchard, C. A., et al. (2010) · Cell · doi:10.1016/j.cell.2009.12.040 · Cited by 1,497 · cited 2×
“This finding is consistent with recent reports that CRAF plays a critical role in RAS-driven lung carcinoma and melanoma (24-26).”
ResultRas oncogenes: split personalities
Karnoub, A. E., & Weinberg, R. A. (2008) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2438 · Cited by 1,467 · cited 1×
“Many KRAS effectors, including RAF, PI3K, RAL and RAC, have RAS-independent means of activation (36), which can be circumvented through direct targeting of effector nodes in addition to KRAS.”
BackgroundAltered cell cycle arrest and gene amplification potential accompany loss of wild-type p53
Livingstone, L. R., White, A., Sprouse, J., Livanos, E., Jacks, T., & Tlsty, T. D. (1992) · Cell · doi:10.1016/0092-8674(92)90243-6 · Cited by 1,328 · cited 9×
“Trp53 -/-MEFs (21) were grown in DMEM supplemented with 10% FBS. KRAS -/-MEFs were obtained from Dr. Mariano Barbacid (CNIO).”
BackgroundMethodInfluential
Cited by
Sorted by citations
Exosomes facilitate therapeutic targeting of oncogenic KRAS in pancreatic cancer
Kamerkar, S., LeBleu, V. S., Sugimoto, H., Yang, S., Ruivo, C. F., Melo, S. A., Lee, J. J., & Kalluri, R. (2017) · Nature · doi:10.1038/nature22341 · Cited by 2,639
RAS Proteins and Their Regulators in Human Disease
Simanshu, D. K., Nissley, D. V., & McCormick, F. (2017) · Cell · doi:10.1016/j.cell.2017.06.009 · Cited by 1,943
Self-citationRAS isoforms and mutations in cancer at a glance
Hobbs, G. A., Der, C. J., & Rossman, K. L. (2016) · Journal of Cell Science · doi:10.1242/jcs.182873 · Cited by 973
“…metabolism), (v) unbiased genetic or chemical screens for synthetic lethal interactors (Barbie et al., 2009; 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).”
BackgroundRole of oncogenic KRAS in the diagnosis, prognosis and treatment of pancreatic cancer
Buscail, L., Bournet, B., & Cordelier, P. (2020) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-019-0245-4 · Cited by 721
Genetics and biology of pancreatic ductal adenocarcinoma
Ying, H., Dey, P., Yao, W., Kimmelman, A. C., Draetta, G. F., Maitra, A., & DePinho, R. A. (2016) · Genes & Development · doi:10.1101/gad.275776.115 · Cited by 527
microRNA Therapeutics in Cancer — An Emerging Concept
Shah, M., Ferrajoli, A., Sood, A. K., Lopez‐Berestein, G., & Călin, G. A. (2016) · EBioMedicine · doi:10.1016/j.ebiom.2016.09.017 · Cited by 461
“For example, it was demonstrated the applicability of ‘sensor’ siRNAs, a universal platform for the combination RNAi therapeutics, in targeting the complete RAF node (KRAS + PIK3CA/B) to treat KRAS-mutant colorectal cancer (Yuan et al., 2014).”
BackgroundClinical experiences with systemically administered siRNA-based therapeutics in cancer
Zuckerman, J. E., & Davis, M. E. (2015) · Nature Reviews Drug Discovery · doi:10.1038/nrd4685 · Cited by 437
KRAS mutation in pancreatic cancer
Luo, J. (2021) · Seminars in Oncology · doi:10.1053/j.seminoncol.2021.02.003 · Cited by 360
“These include the use of siRNAs against KRAS (25), the use of mutant KRAS peptide for anticancer vaccine (26, 27), and the development of adoptive T-cell therapy with T-cell receptors that specifically react to mutant KRAS peptides (28, 29).”
BackgroundSelf-citationMcCormick, F. (2015) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-14-2662 · Cited by 320
“Efficacy was improved by the addition of siRNA targeting PI3K in the same particle (30).”
BackgroundSelf-citationExosome-guided bone targeted delivery of Antagomir-188 as an anabolic therapy for bone loss
Hu, Y., Li, X., Zhang, Q., Gu, Z., Luo, Y., Guo, J., Wang, X., Jing, Y., Chen, X., & Su, J. (2021) · Bioactive Materials · doi:10.1016/j.bioactmat.2021.02.014 · Cited by 215
Drugging Ras GTPase: a comprehensive mechanistic and signaling structural view
Lu, S., Jang, H., Gu, S., Zhang, J., & Nussinov, R. (2016) · Chemical Society Reviews · doi:10.1039/c5cs00911a · Cited by 188
RAS: Striking at the Core of the Oncogenic Circuitry
Gimple, R. C., & Wang, X. (2019) · Frontiers in Oncology · doi:10.3389/fonc.2019.00965 · Cited by 174
“Optimized siRNAs targeting KRAS impaired colon cancer growth in vivo while combinatorial inhibition of KRAS and PIK3CA/PIK3CB significantly improved tumor control compared to single agents alone, demonstrating that targets can be effectively multiplexed (106).”
BackgroundPrediction of potent shRNAs with a sequential classification algorithm
Pelossof, R., Fairchild, L., Huang, C., Widmer, C., Sreedharan, V. T., Sinha, N., Lai, D.-Y., Guan, Y., Premsrirut, P. K., Tschaharganeh, D. F., et al. (2017) · Nature Biotechnology · doi:10.1038/nbt.3807 · Cited by 185
Self-citationKRAS Mutant Pancreatic Cancer: No Lone Path to an Effective Treatment
Zeitouni, D., Pylayeva‐Gupta, Y., Der, C. J., & Bryant, K. L. (2016) · Cancers · doi:10.3390/cancers8040045 · Cited by 191
Clinical Advances of siRNA-Based Nanotherapeutics for Cancer Treatment
Hattab, D., Gazzali, A. M., & Bakhtiar, A. (2021) · Pharmaceutics · doi:10.3390/pharmaceutics13071009 · Cited by 154
“revealed that simultaneous delivery and suppression of multiple gene/protein targets (KRAS, PIK3CA, and PIK3CB) inhibits tumor growth, significantly surpassing the inhibition caused by administration of high doses of a single anti-KRAS siRNA [67].”
BackgroundDifferential effector engagement by oncogenic KRAS
Yuan, T. L., Amzallag, A., Bagni, R., Yi, M., Afghani, S., Burgan, W., Fer, N., Strathern, L. A., Powell, K., Smith, B., et al. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.01.051 · Cited by 150
“Small-interfering RNAs (siRNAs) were designed using RNAi Sensor assay technology against RAS pathway genes (Fellmann et al., 2011; Pelossof et al., 2017; Yuan et al., 2014) (Table S1, Figure S1A-B).”
MethodSelf-citationMAP kinase and autophagy pathways cooperate to maintain RAS mutant cancer cell survival
Lee, C.-S., Lee, L. C., Yuan, T. L., Chakka, S., Fellmann, C., Lowe, S. W., Caplen, N. J., McCormick, F., & Luo, J. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1817494116 · Cited by 126
“knockdown of up to seven genes in the cell (29).”
BackgroundMethodInfluentialSelf-citationMutant KRAS as a critical determinant of the therapeutic response of colorectal cancer
Knickelbein, K., & Zhang, L. (2014) · Genes & Diseases · doi:10.1016/j.gendis.2014.10.002 · Cited by 124
Wan, T. Y., Chen, Y., Pan, Q., Xu, X., Kang, Y., Gao, X., Huang, F., Wu, C., & Yuan, P. (2020) · Journal of Controlled Release · doi:10.1016/j.jconrel.2020.03.015 · Cited by 117
Targeted siRNA lipid nanoparticles for the treatment of KRAS-mutant tumors
Anthiya, S., Öztürk, S. C., Yanık, H., Tavukçuoğlu, E., Şahin, A., Datta, D., Charissé, K., Moreira, D., Loza, M. I., Calvo, A., et al. (2023) · Journal of Controlled Release · doi:10.1016/j.jconrel.2023.03.016 · Cited by 102
“1–2 nM concentration) with the least off-target effects [1].”
BackgroundInfluentialGu, L., Deng, Z. J., Roy, S., & Hammond, P. T. (2017) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-16-2186 · Cited by 99
Therapeutic trends in pancreatic ductal adenocarcinoma (PDAC)
Chandana, S. R., Babiker, H. M., & Mahadevan, D. (2018) · Expert Opinion on Investigational Drugs · doi:10.1080/13543784.2019.1557145 · Cited by 102
“KRAS expression had been explored in mutant mouse models of cancer [50,51] and has shown tumor proliferation and”
BackgroundSynthetic Lethal Vulnerabilities in KRAS-Mutant Cancers
Aguirre, A. J., & Hahn, W. C. (2018) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a031518 · Cited by 90
“…has been shown to mediate tumor cell proliferation and survival in a variety of in vitro and in vivo experiments (Blasco et al. 2011; Karreth et al. 2011; Collisson et al. 2012; Yuan et al. 2014), and numerous small molecule inhibitors of this pathway are in clinical development (Ryan et al. 2015).”
BackgroundKirsten Ras* oncogene: Significance of its discovery in human cancer research
Tsuchida, N., Murugan, A. K., & Grieco, M. (2016) · Oncotarget · doi:10.18632/oncotarget.8773 · Cited by 94
Nanoparticles for siRNA-Based Gene Silencing in Tumor Therapy
Babu, A., Muralidharan, R., Amreddy, N., Mehta, M., Munshi, A., & Ramesh, R. (2016) · IEEE Transactions on NanoBioscience · doi:10.1109/tnb.2016.2621730 · Cited by 84
“RNA interference technology (RNAi) has been highly successful in exploring these druggable targets [6], [7], [8], but the real advantage of RNAi is that it can even target disease-causing genes that are considered “non-druggable” [9], [10].”
BackgroundExosomes in Precision Oncology and Beyond: From Bench to Bedside in Diagnostics and Therapeutics
Youssef, E. M., Palmer, D., Fletcher, B., & Vaughn, R. (2025) · Cancers · doi:10.3390/cancers17060940 · Cited by 85
Liposome technologies towards colorectal cancer therapeutics
Sang, R., Stratton, B., Engel, A. F., & Deng, W. (2021) · Acta Biomaterialia · doi:10.1016/j.actbio.2021.03.055 · Cited by 70
Direct Pharmacological Inhibition of β-Catenin by RNA Interference in Tumors of Diverse Origin
Ganesh, S., Koser, M. L., Cyr, W. A., Chopda, G. R., Tao, J., Shui, X., Ying, B., Chen, D., Pandya, P., Chipumuro, E., et al. (2016) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-16-0309 · Cited by 62
“Other nonlipid-based RNAi delivery vehicles, including cyclodextrin polymers (54), have also shown promise in preclinical tumor models, although early clinical development appears to have stalled (20).”
KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance
Ash, L. J., Busia-Bourdain, O., Okpattah, D., Kamel, A., Liberchuk, A., & Wolfe, A. L. (2024) · Current Oncology · doi:10.3390/curroncol31040150 · Cited by 68
Shen, H., Lundy, J., Strickland, A. H., Harris, M., Swan, M. P., Desmond, C., Jenkins, B. J., & Croagh, D. G. (2022) · Cells · doi:10.3390/cells11193175 · Cited by 58
“Another approach includes siG12D-LODERTM, an siRNA which targets KRAS loaded into a biodegradable polymetric matrix [30].”
BackgroundTargeting the undruggable oncogenic KRAS: the dawn of hope
Asimgil, H., Ertetik, U., Çevik, N. C., Ekizce, M., Doğruöz, A., Gökalp, M., Sever, E. A., Istvánffy, R., Friess, H., Ceyhan, G. O., et al. (2022) · JCI Insight · doi:10.1172/jci.insight.153688 · Cited by 57
Dietrich, P., Kuphal, S., Spruß, T., Hellerbrand, C., & Bosserhoff, A. (2017) · Oncogene · doi:10.1038/onc.2017.391 · Cited by 54
Vivekanandhan, S., & Mukhopadhyay, D. (2018) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2018.01.014 · Cited by 53
“PI3K phosphorylates the phosphoinositides present at the third position in an inositol ring.”
BackgroundInfluentialTargeting KRAS mutations: orchestrating cancer evolution and therapeutic challenges
Choucair, K., Imtiaz, H., Uddin, M. H., Nagasaka, M., Al-Hallak, M. N., Philip, P. A., El-Rayes, B., Pasche, B., & Azmi, A. S. (2025) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-025-02473-8 · Cited by 67
Targeting KRAS mutations in pancreatic cancer: opportunities for future strategies
Linehan, A., O’Reilly, M., McDermott, R., & O'Kane, G. M. (2024) · Frontiers in Medicine · doi:10.3389/fmed.2024.1369136 · Cited by 57
Selective targeting of point-mutated KRAS through artificial microRNAs
Acunzo, M., Romano, G., Nigita, G., Veneziano, D., Fattore, L., Laganà, A., Zanesi, N., Fadda, P., Fassan, M., Rizzotto, L., et al. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1620562114 · Cited by 48
“Several attempts to target KRAS-mutant cancers have used small noncoding RNA (sncRNA), in particular, small-interfering RNA (siRNA) targeting KRAS pathways (8).”
BackgroundEfficient Correction of Oncogenic KRAS and TP53 Mutations through CRISPR Base Editing
Sayed, S., Sidorova, O. A., Hennig, A., Augsburg, M., Vesga, C. P. C., Abohawya, M., Schmitt, L. T., Sürün, D., Stange, D. E., Mircetic, J., et al. (2022) · Cancer Research · doi:10.1158/0008-5472.can-21-2519 · Cited by 51
Targeting KRAS in Solid Tumors: Current Challenges and Future Opportunities of Novel KRAS Inhibitors
Indini, A., Rijavec, E., Ghidini, M., Cortellini, A., & Grossi, F. (2021) · Pharmaceutics · doi:10.3390/pharmaceutics13050653 · Cited by 49
“The Local Drug Eluter (LODER) is a biodegradable polymeric matrix that protects the siRNA and enables its local release over a period of months within the tumor tissues [50].”
BackgroundNext-generation therapies for pancreatic cancer
Buckley, C. W., & O'Reilly, E. M. (2024) · Expert Review of Gastroenterology & Hepatology · doi:10.1080/17474124.2024.2322648 · Cited by 49
“RNA interference (RNAi) utilizes short non-coding strands of RNA, known as short interfering RNA (SiRNA) or microRNA (miRNA), to selectively block the translation of messenger RNA (mRNA) from specific oncogenes [95].”
BackgroundZhao, G., Ho, W., Chu, J., Xiong, X., Hu, B., Boakye‐Yiadom, K. O., Xu, X., & Zhang, X. (2023) · ACS Applied Materials & Interfaces · doi:10.1021/acsami.3c05007 · Cited by 43
Targeting Mutant KRAS in Pancreatic Cancer: Futile or Promising?
Nollmann, F. I., & Ruess, D. A. (2020) · Biomedicines · doi:10.3390/biomedicines8080281 · Cited by 33
Ng, S., Juang, Y.-C. A., Chandramohan, A., Kaan, H. Y. K., Sadruddin, A., Yuen, T. Y., Ferrer‐Gago, F. J., Lee, X. C., Liew, X., Johannes, C. W., et al. (2020) · ACS Medicinal Chemistry Letters · doi:10.1021/acsmedchemlett.0c00022 · Cited by 35
Chen, K., Shang, Z., Dai, A.-L., & Dai, P.-L. (2020) · Life Sciences · doi:10.1016/j.lfs.2020.117816 · Cited by 33
Let-7 Sensitizes KRAS Mutant Tumor Cells to Chemotherapy
Dai, X., Jiang, Y., & Tan, C. (2015) · PLoS ONE · doi:10.1371/journal.pone.0126653 · Cited by 29
“Nevertheless, the downregulation of mutant KRAS by let-7b alone was insufficient to block the proliferation of KRAS mutant cells nor did it induce appreciable apoptosis, consistent with the findings that knockdown of mutant KRAS using siRNAs had limited antitumor effect in vitro and in vivo [19,36].”
ResultBeneker, C. M., Rovoli, M., Kontopidis, G. A., Röring, M., Galda, S., Braun, S. L., Brummer, T., & McInnes, C. (2019) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.8b01288 · Cited by 29
From basic researches to new achievements in therapeutic strategies of KRAS-driven cancers
Saliani, M., Jalal, R., & Ahmadian, M. R. (2019) · Cancer Biology and Medicine · doi:10.20892/j.issn.2095-3941.2018.0530 · Cited by 27
Targeting KRAS in Pancreatic Cancer
Cowzer, D., Zameer, M., Conroy, M. R., Kölch, W., & Duffy, A. G. (2022) · Journal of Personalized Medicine · doi:10.3390/jpm12111870 · Cited by 34
“RNAi techniques have been under investigation as a tool to silence the expression of oncogenes and signaling effectors [51].”
MethodHuang, Z., Liu, M., Li, D., Tan, Y., Zhang, R., Xia, Z., Wang, P., Jiao, B., Liu, P., & Ren, R. (2020) · Journal of Biological Chemistry · doi:10.1074/jbc.ra119.011060 · Cited by 27
Yang, L., Li, Z., Binzel, D. W., Guo, P., & Williams, T. M. (2023) · Molecular Therapy — Nucleic Acids · doi:10.1016/j.omtn.2023.07.027 · Cited by 29
The genomic landscape of metastasis in treatment-naïve breast cancer models
Ross, C. R., Szczepanek, K., Lee, M. Y., Yang, H. H., Qiu, T., Sanford, J. D., & Hunter, K. W. (2020) · PLoS Genetics · doi:10.1371/journal.pgen.1008743 · Cited by 25
The roles and mechanisms of coding and noncoding RNA variations in cancer
Kim, S. Y., Na, M. J., Yoon, S., Shin, E., Ha, J. W., Jeon, S., & Nam, S. W. (2024) · Experimental & Molecular Medicine · doi:10.1038/s12276-024-01307-x · Cited by 25
“Numerous therapeutic programs targeting various oncogenes and pathways, including KRAS mutants, VEGF, MYC oncogene, and PLK1, are underway 19 – 21 .”
BackgroundNanomaterials Respond to Lysosomal Function for Tumor Treatment
Tian, X., Shi, A., Yin, H. H., Wang, Y., Liu, Q., Chen, W., & Wu, J. (2022) · Cells · doi:10.3390/cells11213348 · Cited by 23
“It has the potential to treat a variety of diseases, including tumors [90].”
BackgroundAdvances in the Genetics and Biology of Pancreatic Cancer
Aguirre, A. J., & Collisson, E. A. (2017) · The Cancer Journal · doi:10.1097/ppo.0000000000000286 · Cited by 23
Yaqoob, A., Li, W. M., Liu, V., Wang, C., Mackedenski, S. J., Tackaberry, L. E., Massicotte, H. B., Egger, K. N., Reimer, K. B., & Lee, C. H. (2020) · PLoS ONE · doi:10.1371/journal.pone.0231948 · Cited by 23
Self-citationMurugananthkumar, R., & Senthilkumaran, B. (2016) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2016.05.006 · Cited by 23
“At the same time, numerous reports represented synthetic siRNA can 556 induce gene-specific inhibition, in vitro and in vivo with respect to several developmental 557 pathways (Yuan et al., 2014).”
BackgroundInducing Oncoprotein Degradation to Improve Targeted Cancer Therapy
Ray, D., Cuneo, K. C., Rehemtulla, A., Lawrence, T. S., & Nyati, M. K. (2015) · Neoplasia · doi:10.1016/j.neo.2015.08.008 · Cited by 22
“Along this point, a recent report demonstrated better in vivo tumor control when mutant KRAS siRNA was combined with either RAF or PI3K siRNAs [34].”
Pan, T., Zhang, Y., Zhou, N., He, X., Chen, C., Liang, L., Duan, X., Lin, Y., Wu, K., & Zhang, H. (2016) · Oncotarget · doi:10.18632/oncotarget.9996 · Cited by 21
Evolution of direct RAS inhibitors: from undruggable target to clinical breakthroughs
Wang, X., Wu, J., Xiao, A., Wang, J., & Tian, J. (2025) · Molecular Cancer · doi:10.1186/s12943-025-02364-0 · Cited by 25
Clinical update on K-Ras targeted therapy in gastrointestinal cancers
Pant, S., Hubbard, J. M., Martinelli, E., & Bekaii‐Saab, T. (2018) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2018.07.011 · Cited by 21
Multiplexed CRISPR/Cas9 gene knockout with simple crRNA:tracrRNA co-transfection
Khan, F. J., Yuen, G., & Luo, J. (2019) · Cell & Bioscience · doi:10.1186/s13578-019-0304-0 · Cited by 21
Self-citationSilencing of Oncogenic KRAS by Mutant-Selective Small Interfering RNA
Papke, B., Azam, S. H., Feng, A. Y., Gutierrez-Ford, C., Huggins, H., Pallan, P. S., Van Swearingen, A. E. D., Egli, M., Cox, A. D., Der, C. J., et al. (2021) · ACS Pharmacology & Translational Science · doi:10.1021/acsptsci.0c00165 · Cited by 22
A brief history of RAS and the RAS Initiative
McCormick, F. P. (2022) · Advances in cancer research · doi:10.1016/bs.acr.2021.07.003 · Cited by 20
Self-citationKRAS, YWHAE, SP1 and MSRA as biomarkers in endometrial cancer
Yang, Y., Sang, Z., Ma, J., Zhu, Y., & Wu, S. (2021) · Translational Cancer Research · doi:10.21037/tcr-20-2969 · Cited by 19
“KRAS-driven tumor regression and growth impaired was observed after nanoparticle-mediated delivery of siKRAS to KRAS-Mutant tumors in a mouse model (33,34), KRAS mutants knockout leads to inhibition of upstream signaling pathways (35,36).”
BackgroundRen, S.-N., Zhang, Z.-Y., Guo, R.-J., Wang, D., Chen, F., Chen, X., & Fang, X. (2023) · World Journal of Gastroenterology · doi:10.3748/wjg.v29.i13.1911 · Cited by 19
Cyclodextrins as Active Therapeutic Agents: Beyond Their Role as Excipients
Pîrvu, A. S., Văruţ, R.-M., Trașcă, D.-M., Stoica, G. A., Radivojević, K., Carmen, S., Arsenie, C. C., & Popescu, C. (2025) · Pharmaceuticals · doi:10.3390/ph18101592 · Cited by 22
MiRNA therapeutics based on logic circuits of biological pathways
Boscaino, V., Fiannaca, A., Paglia, L. L., Rosa, M. L., Rizzo, R., & Urso, A. M. (2019) · BMC Bioinformatics · doi:10.1186/s12859-019-2881-7 · Cited by 17
The potential of targeting Ras proteins in lung cancer
McCormick, F. P. (2015) · Expert Opinion on Therapeutic Targets · doi:10.1517/14728222.2014.1000304 · Cited by 17
“Similar results have been reported by Jacks, and coworkers [9,10].”
ResultSelf-citationAlagesan, B., Varghese, A. M., Ang, C., Gutiérrez, M., Kamar, M., Passhak, M., Geva, R., Yarom, N., Lahav, M., Ligresti, R., et al. (2026) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-25-3189 · Cited by 19
Computational design and validation of effective siRNAs to silence oncogenic KRAS
Ramalingam, P. S., & Arumugam, S. (2023) · 3 Biotech · doi:10.1007/s13205-023-03767-w · Cited by 18
“The mutation in RAS proteins leads to the progression of pancreatic, lung, colon, and breast cancers with more aggressiveness (Fernández-Medarde and Santos 2011; Zeitouni et al. 2016).”
BackgroundTargeting Mutant KRAS for Anticancer Therapy
Chen, F., Alphonse, M. P., Liu, Y., & Liu, Q. (2019) · Current Topics in Medicinal Chemistry · doi:10.2174/1568026619666190902151307 · Cited by 15
Current views on inducing synthetic lethal RNAi responses in the treatment of cancer
Kacsinta, A. D., & Dowdy, S. F. (2015) · Expert Opinion on Biological Therapy · doi:10.1517/14712598.2016.1110141 · Cited by 15
Targeting Ras with MacromoleculesPreprint
Pei, D., Chen, K., & Liao, H. (2017) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a031476 · Cited by 15
“Finally, siRNA against mutant K-Ras has been used in combination with siRNAs against other Ras signaling pathway targets (e.g., Raf and PI3K) to treat colorectal cancer in xenograft models (Yuan et al. 2014).”
Novel RAF ‐directed approaches to overcome current clinical limits and block the RAS / RAF node
Scardaci, R., Berlinska, E., Scaparone, P., Michelina, S. V., Garbo, E., Novello, S., Santamarı́a, D., & Ambrogio, C. (2024) · Molecular Oncology · doi:10.1002/1878-0261.13605 · Cited by 14
“Indeed, while for a long time attempts to target RAS utilizing its downstream effectors were unsuccessful, in the recent years, novel findings justi-fied the rationale of using RAF inhibitors in RAS mutant tumors as well [204].”
BackgroundHan, Z., Zhou, D., Wang, J., Jiang, B., & Liu, X. (2022) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2022.188677 · Cited by 13
Ductal activation of oncogenic KRAS alone induces sarcomatoid phenotype
Fu, Y., Cruz‐Monserrate, Z., Lin, H. H., Chung, Y., Ji, B., Lin, S.-M., Vonderfecht, S. L., Logsdon, C. D., Li, C., & Ann, D. K. (2015) · Scientific Reports · doi:10.1038/srep13347 · Cited by 13
“Rabbit anti-elastase I polyclonal antibody was from Life Span BioSciences, Inc. Biotin rat anti-mouse CD45 (53078), rat anti-mouse Ly-6G and Ly-6C (Gr-1) (550291) were from BD Biosciences and anti-mouse F4/80 (14-4801) was from eBioscience.”
MethodInfluentialAdvances in Novel Targeted Therapies for Pancreatic Adenocarcinoma
Hoang, T. A., & Tsang, E. S. (2025) · Journal of Gastrointestinal Cancer · doi:10.1007/s12029-024-01149-w · Cited by 15
Endogenous spacing enables co-processing of microRNAs and efficient combinatorial RNAi
Amen, A. M., Loughran, R. M., Huang, C., Lew, R. J., Ravi, A., Guan, Y., Schatoff, E. M., Dow, L. E., Emerling, B. M., & Fellmann, C. (2022) · Cell Reports Methods · doi:10.1016/j.crmeth.2022.100239 · Cited by 12
“Use of microRNA-embedded shRNAs driven by RNA polymerase II (Pol-II) promoters overcomes these limitations (Baek et al., 2014; Boudreau et al., 2008; McBride et al., 2008), especially when used at singlecopy genomic integration (Fellmann et al., 2011; Yuan et al., 2014).”
BackgroundInfluentialSelf-citationNatural and artificial small RNAs: a promising avenue of nucleic acid therapeutics for cancer
Yadav, S., Shekhawat, M., Jahagirdar, D., & Kumar, S. N. (2017) · Cancer Biology and Medicine · doi:10.20892/j.issn.2095-3941.2017.0038 · Cited by 12
MicroRNA‐Based Therapeutic Strategies for Targeting Mutant and Wild Type RAS in Cancer
Sharma, S. B., & Ruppert, J. M. (2015) · Drug Development Research · doi:10.1002/ddr.21270 · Cited by 11
“Other ongoing approaches include reovirus-based therapies and siRNA therapy against mutant KRAS [Thirukkumaran and Morris, 2009; Zorde et al., 2013; Yuan et al., 2014; Golan et al., 2015].”
BackgroundInfluentialmiRNAs in Lymphocytic Leukaemias—The miRror of Drug Resistance
Sbirkov, Y., Vergov, B., Mehterov, N. H., & Sarafian, V. S. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23094657 · Cited by 10
Shin, W., Lee, S.-K., Hwang, J.-H., Park, J.-C., Cho, Y.-H., Ro, E. J., Song, Y., Seo, H. R., & Choi, K.-Y. (2018) · Experimental & Molecular Medicine · doi:10.1038/s12276-018-0102-5 · Cited by 10
Nucleic Acid-Based Approaches to Tackle KRAS Mutant Cancers
Kim, J. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms242316933 · Cited by 9
“These siRNAs have demonstrated a selective reduction in the growth of tumors that are dependent on KRAS mutations [36–40]; however, their clinical translation has been hindered by intracellular and extracellular barriers.”
BackgroundShao, Y., Ma, L., Zhang, T., Xu, T., Ye, Y., & Liu, Y. (2019) · Current Topics in Medicinal Chemistry · doi:10.2174/1568026619666190828162217 · Cited by 12
Wen, Q., Dunne, P. D., O’Reilly, P. G., Li, G., Bjourson, A. J., McArt, D. G., Hamilton, P. W., & Zhang, S. (2016) · Oncotarget · doi:10.18632/oncotarget.13884 · Cited by 9
Downregulation of PIK3CA via antibody-esiRNA-complexes suppresses human xenograft tumor growth
Bäumer, N., Rehkämper, J., Appel, N., Terheyden, L., Hartmann, W., Wardelmann, E., Buchholz, F., Müller‐Tidow, C., Berdel, W. E., & Bäumer, S. (2018) · PLoS ONE · doi:10.1371/journal.pone.0200163 · Cited by 9
Nanoparticle-mediated delivery of siRNA: Targeting gene silencing in cancer therapy
Udappusamy, V., Thangam, S. N., Ramasamy, N. K., Ganeshan, S., Rajan, D. K., & Moovendhan, M. (2025) · Journal of Drug Delivery Science and Technology · doi:10.1016/j.jddst.2025.106973 · Cited by 9
shRNAI: A deep neural network for the design of highly potent shRNAs
Park, S., Park, S.-H., Oh, J.-S., Hong, S., Been, K. W., Noh, Y., Hur, J. K., & Nam, J. (2025) · Molecular Therapy — Nucleic Acids · doi:10.1016/j.omtn.2025.102738 · Cited by 8
“In previous shRNA screening studies 55,58–60, 64, 66– 81 These insights suggest that further improvements may be achieved by better modeling in vivo Drosha/Dicer processing efficiency, pre-shRNA export, and AGO loading efficiency.”
Zhang, H., Read, A., Cataisson, C., Yang, H. H., Lee, W., Turk, B. E., Yuspa, S. H., & Luo, J. (2024) · Science Signaling · doi:10.1126/scisignal.add5073 · Cited by 8
“This library was transduced into SW620, a CRC cell line that harbors a KRAS G12V mutation and is KRAS dependent ( 38 ).”
BackgroundSelf-citationBavishi, L., Butani, S., & Patel, S. S. (2025) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2025.178198 · Cited by 8
Burska, A. N., Ilyassova, B., Dildabek, A., Khamijan, M., Бегимбетова, Д., Molnár, F., & Sarbassov, D. D. (2022) · Cells · doi:10.3390/cells11213454 · Cited by 7
“The RNA interference approach to silence KRAS oncogene expression was also tested [63,64].”
MethodCancer biology functional genomics: From small RNAs to big dreams
Rajan, S. S., Ludwig, K. R., Hall, K. L., Jones, T. L., & Caplen, N. J. (2020) · Molecular Carcinogenesis · doi:10.1002/mc.23260 · Cited by 6
“quence algorithm and a screening workflow that pooled siRNAs targeting multiple genes.(71,126) This study demonstrated that the combined targeting of RAF‐kinase signaling (BRAF and CRAF/RAF1) and autophagy (autophagy E1 ligase ATG7) induces G1‐arrest and apoptosis of KRAS‐mutant cells while mediating minimal effects o…”
MethodRas proteins as therapeutic targets
Chakraborty, A., Linnane, E., & Ross, S. J. (2018) · Biochemical Society Transactions · doi:10.1042/bst20170529 · Cited by 6
Efficacy of siRNA-loaded nanoparticles in the treatment of K-RAS mutant lung cancerin vitro
Gencer, A., Baysal, İ., Nemutlu, E., Ciftci, S. Y., & Arıca, B. (2022) · Journal of Microencapsulation · doi:10.1080/02652048.2022.2061058 · Cited by 5
RAS: Circuitry and therapeutic targeting
Singh, G., Thakur, N., & Kumar, U. (2022) · Cellular Signalling · doi:10.1016/j.cellsig.2022.110505 · Cited by 6
Vaishnavi, S., Bhatt, C. S., & Ellipilli, S. (2025) · Molecular Pharmaceutics · doi:10.1021/acs.molpharmaceut.5c00733 · Cited by 5
How Can Next-Generation Diagnostics Aid Pancreatic Adenocarcinoma Treatment?
Zhang, S. Q., & Catenacci, D. V. T. (2016) · Future Oncology · doi:10.2217/fon.15.353 · Cited by 3
McCormick, F. P. (2026) · Biological Chemistry · doi:10.1515/hsz-2025-0244 · Cited by 2
Self-citationSahu, P., Mitra, A., & Ganguly, A. (2024) · International review of cytology · doi:10.1016/bs.ircmb.2024.01.005 · Cited by 2
Could Drug Delivery Systems Be Enhancers for Therapy against KRAS-driven Cancers?
Khusnutdinov, R. (2024) · Reviews and Advances in Chemistry · doi:10.1134/s2634827624600312 · Cited by 2
Molecular Diagnostics and Genomic Profiling in Individualized Therapies of Gastrointestinal Cancers
Kamgar, M., & Korn, W. M. (2019) · Springer eBooks · doi:10.1007/978-3-030-18890-0_34 · Cited by 1
Metadata
- Authors
- Yuan, T. L., Fellmann, C., Lee, C.-S., Ritchie, C. D., Thapar, V., Lee, L. C., Hsu, D. J., Grace, D., Carver, J. O., Zuber, J., Luo, J., McCormick, F., & Lowe, S. W.
- Affiliations
- University of California, San Francisco (US)
- Cold Spring Harbor Laboratory (US)
- National Cancer Institute (US)
- Memorial Sloan Kettering Cancer Center (US)
- Research Institute of Molecular Pathology (AT)
- Corresponding author
- Luo, Ji
- McCormick, Frank
- Lowe, Scott W.
- ORCID
- Venue
- Cancer Discovery
- Published
- 2014-09-30
- Volume
- 4
- Issue
- 10
- Pages
- 1182-1197
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- PMC
- PMC4184972
- OpenAlex
- W2098360608
- Cited by
- 113
- References
- 39
- Citations by year
- 2026: 4 · 2025: 9 · 2024: 8 · 2023: 7 · 2022: 12 · 2021: 8 · 2020: 10 · 2019: 12 · 2018: 9 · 2017: 12 · 2016: 12 · 2015: 9 · 2014: 1
- FWCI
- 4.65
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Discovery (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Cold Spring Harbor Laboratory Institutional Repository (Cold Spring Harbor Laboratory) (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institutes of Health
- U.S. Public Health Service (1ZIABC011437)
- National Cancer Institute (ZIABC011437, U01CA168409, U01CA168370, T32CA108462, P01CA013106, P30CA008748)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › CRISPR and Genetic Engineering
- Keywords
- siRNA, KRAS mutation, RNAi therapeutics, siRNA delivery, siRNA library, Ras signaling, Raf-1, PIK3CA, PIK3CB, colorectal cancer, off-target effects, xenograft models
- MeSH terms
- Animals, Disease Models, Animal, Humans, Mutation, Neoplasms, Genes, ras, Reproducibility of Results, Signal Transduction, Gene Library, Cluster Analysis, Drug Delivery Systems, Gene Transfer Techniques, Phosphatidylinositol 3-Kinases, Gene Expression Profiling, Xenograft Model Antitumor Assays, RNA Interference, RNA, Small Interfering, Cell Line, Tumor, Tumor Burden, Mice, Nanoparticles, Gene Knockdown Techniques
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