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XPO1-dependent nuclear export is a druggable vulnerability in KRAS-mutant lung cancer
Open accessAbstract
The common participation of oncogenic KRAS proteins in many of the most lethal human cancers, together with the ease of detecting somatic KRAS mutant alleles in patient samples, has spurred persistent and intensive efforts to develop drugs that inhibit KRAS activity. However, advances have been hindered by the pervasive inter- and intra-lineage diversity in the targetable mechanisms that underlie KRAS-driven cancers, limited pharmacological accessibility of many candidate synthetic-lethal interactions and the swift emergence of unanticipated resistance mechanisms to otherwise effective targeted therapies. Here we demonstrate the acute and specific cell-autonomous addiction of KRAS-mutant non-small-cell lung cancer cells to receptor-dependent nuclear export. A multi-genomic, data-driven approach, utilizing 106 human non-small-cell lung cancer cell lines, was used to interrogate 4,725 biological processes with 39,760 short interfering RNA pools for those selectively required for the survival of KRAS-mutant cells that harbour a broad spectrum of phenotypic variation. Nuclear transport machinery was the sole process-level discriminator of statistical significance. Chemical perturbation of the nuclear export receptor XPO1 (also known as CRM1), with a clinically available drug, revealed a robust synthetic-lethal interaction with native or engineered oncogenic KRAS both in vitro and in vivo. The primary mechanism underpinning XPO1 inhibitor sensitivity was intolerance to the accumulation of nuclear IκBα (also known as NFKBIA), with consequent inhibition of NFκB transcription factor activity. Intrinsic resistance associated with concurrent FSTL5 mutations was detected and determined to be a consequence of YAP1 activation via a previously unappreciated FSTL5-Hippo pathway regulatory axis. This occurs in approximately 17% of KRAS-mutant lung cancers, and can be overcome with the co-administration of a YAP1-TEAD inhibitor. These findings indicate that clinically available XPO1 inhibitors are a promising therapeutic strategy for a considerable cohort of patients with lung cancer when coupled to genomics-guided patient selection and observation.
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“The pervasive diversity of this oncogenotype was aptly demonstrated in a study that applied affinity propagation clustering analysis36 to mRNA expression data from 106 genomically-annotated NSCLC cell lines; strikingly, variation in mRNA expression within KRAS-mutant NSCLC cell lines was equivalent to that observed across the entire cell line panel37.”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [37]
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Cites
Cytoscape: A software Environment for integrated models of biomolecular interaction networks
Shannon, P., Markiel, A., Ozier, O., Baliga, N. S., Wang, J. T., Ramage, D., Amin, N., Schwikowski, B., & Ideker, T. (2003) · Genome Research · doi:10.1101/gr.1239303 · Cited by 51,888
Ultrafast and memory-efficient alignment of short DNA sequences to the human genome.
Langmead, B., Trapnell, C., Pop, M., & Salzberg, S. L. (2009) · Genome Biology · doi:10.1186/gb-2009-10-3-r25 · Cited by 21,849
Clustering by Passing Messages Between Data Points
Frey, B. J., & Dueck, D. (2007) · Science · doi:10.1126/science.1136800 · Cited by 6,855
Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1
Barbie, D. A., Tamayo, P., Boehm, J. S., Kim, S. Y., Moody, S. E., Dunn, I. F., Schinzel, A. C., Sandy, P., Meylan, E., Scholl, C., et al. (2009) · Nature · doi:10.1038/nature08460 · Cited by 3,922
Shigematsu, H., Lin, L., Takahashi, T., Nomura, M., Suzuki, M., Wistuba, I. I., Fong, K. M., Lee, H., Toyooka, S., Shimizu, N., et al. (2005) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/dji055 · Cited by 2,377
Self-citationHippo pathway in organ size control, tissue homeostasis, and cancer
Yu, F.-X., Zhao, B., & Guan, K.-L. (2015) · Cell · doi:10.1016/j.cell.2015.10.044 · Cited by 2,206
Drugging the undruggable RAS: Mission Possible?
Cox, A. D., Fesik, S. W., Kimmelman, A. C., Luo, J., & Der, C. J. (2014) · Nature Reviews Drug Discovery · doi:10.1038/nrd4389 · Cited by 1,997
A Genome-wide RNAi Screen Identifies Multiple Synthetic Lethal Interactions with the Ras Oncogene
Luo, J., Emanuele, M. J., Li, D., Creighton, C. J., Schlabach, M. R., Westbrook, T. F., Wong, K.-K., & Elledge, S. J. (2009) · Cell · doi:10.1016/j.cell.2009.05.006 · Cited by 1,017
Widespread siRNA “off-target” transcript silencing mediated by seed region sequence complementarity
Jackson, A. L., Burchard, J., Schelter, J. M., Chau, B. N., Cleary, M. A., Lim, L. P., & Linsley, P. S. (2006) · RNA · doi:10.1261/rna.25706 · Cited by 979
Conditional mouse lung cancer models using adenoviral or lentiviral delivery of Cre recombinase
DuPage, M. J. P., Dooley, A. L., & Jacks, T. (2009) · Nature Protocols · doi:10.1038/nprot.2009.95 · Cited by 873
KRAS and YAP1 Converge to Regulate EMT and Tumor Survival
Shao, D. D., Xue, W., Krall, E. B., Bhutkar, A., Piccioni, F., Wang, X., Schinzel, A. C., Sood, S., Rosenbluh, J., Kim, J. W., et al. (2014) · Cell · doi:10.1016/j.cell.2014.06.004 · Cited by 744
Self-citationYap1 Activation Enables Bypass of Oncogenic Kras Addiction in Pancreatic Cancer
Kapoor, A., Yao, W., Ying, H., Hua, S., Liewen, A., Wang, Q., Zhong, Y., Wu, C.-J., Sadanandam, A., Hu, B., et al. (2014) · Cell · doi:10.1016/j.cell.2014.06.003 · Cited by 716
Somatic Mutations of the HER2 Kinase Domain in Lung Adenocarcinomas
Shigematsu, H., Takahashi, T., Nomura, M., Majmudar, K., Suzuki, M., Lee, H., Wistuba, I. I., Fong, K. M., Toyooka, S., Shimizu, N., et al. (2005) · Cancer Research · doi:10.1158/0008-5472.can-04-4235 · Cited by 678
Self-citationCellular energy stress induces AMPK-mediated regulation of YAP and the Hippo pathway
Mo, J.-S., Meng, Z., Kim, Y. C., Park, H. W., Hansen, C. G., Kim, S., Lim, D.-S., & Guan, K.-L. (2015) · Nature Cell Biology · doi:10.1038/ncb3111 · Cited by 557
The Hippo effector YAP promotes resistance to RAF- and MEK-targeted cancer therapies
Lin, L., Sabnis, A. J., Chan, E., Olivas, V., Cade, L., Pazarentzos, E., Asthana, S., Neel, D., Yan, J. J., Lu, X., et al. (2015) · Nature Genetics · doi:10.1038/ng.3218 · Cited by 551
Burke, J. R., Pattoli, M. A., Gregor, K. R., Brassil, P. J., MacMaster, J. F., McIntyre, K. W., Yang, X., Iotzova, V. S., Clarke, W., Strnad, J., et al. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m209677200 · Cited by 550
Scholl, C., Fröhling, S., Dunn, I. F., Schinzel, A. C., Barbie, D. A., Kim, S. Y., Silver, S. J., Tamayo, P., Wadlow, R. C., Ramaswamy, S., et al. (2009) · Cell · doi:10.1016/j.cell.2009.03.017 · Cited by 546
Requirement for NF-κB signalling in a mouse model of lung adenocarcinoma
Meylan, E., Dooley, A. L., Feldser, D. M., Shen, L., Turk, E., Ouyang, C., & Jacks, T. (2009) · Nature · doi:10.1038/nature08462 · Cited by 514
Synthetic lethal screen identification of chemosensitizer loci in cancer cells
Whitehurst, A. W., Bodemann, B. O., Cardenas, J., Ferguson, D., Girard, L., Peyton, M., Minna, J. D., Michnoff, C. H., Hao, W., Roth, M. G., et al. (2007) · Nature · doi:10.1038/nature05697 · Cited by 471
Self-citationPIK3CA Mutations and Copy Number Gains in Human Lung Cancers
Yamamoto, H., Shigematsu, H., Nomura, M., Lockwood, W. W., Sato, M., Okumura, N., Soh, J., Suzuki, M., Wistuba, I. I., Fong, K. M., et al. (2008) · Cancer Research · doi:10.1158/0008-5472.can-07-5084 · Cited by 443
Self-citationAn Oncogenomics-Based In Vivo RNAi Screen Identifies Tumor Suppressors in Liver Cancer
Zender, L., Xue, W., Zuber, J. A., Semighini, C. P., Krasnitz, A., Ma, B., Zender, P., Kubicka, S., Luk, J. M., Schirmacher, P., et al. (2008) · Cell · doi:10.1016/j.cell.2008.09.061 · Cited by 428
NCI-navy medical oncology branch cell line data base
Phelps, R. M., Johnson, B. E., Ihde, D. C., Gazdar, A. F., Carbone, D. P., McClintock, P. R., Linnoila, R. I., Matthews, M. J., Bunn, P. A., Carney, D. N., et al. (1996) · Journal of Cellular Biochemistry · doi:10.1002/jcb.240630505 · Cited by 304
Self-citationLapalombella, R., Sun, Q., Williams, K., Tangeman, L., Jha, S., Zhong, Y., Goettl, V. M., Mahoney, E., Berglund, C., Gupta, S. V., et al. (2012) · Blood · doi:10.1182/blood-2012-05-429506 · Cited by 304
Self-citationThe GATA2 Transcriptional Network Is Requisite for RAS Oncogene-Driven Non-Small Cell Lung Cancer
Kumar, M. S., Hancock, D. C., Molina‐Arcas, M., Steckel, M., East, P., Diefenbacher, M. E., Armenteros-Monterroso, E., Lassailly, F., Matthews, N., Nye, E. L., et al. (2012) · Cell · doi:10.1016/j.cell.2012.02.059 · Cited by 269
YAP Inhibition Restores Hepatocyte Differentiation in Advanced HCC, Leading to Tumor Regression
Fitamant, J., Kottakis, F., Benhamouche, S., Tian, H. S., Chuvin, N., Parachoniak, C. A., Nagle, J. M., Perera, R. M., Lapouge, M., Deshpande, V., et al. (2015) · Cell Reports · doi:10.1016/j.celrep.2015.02.027 · Cited by 248
Razak, A. R. A., Mau‐Sørensen, M., Gabrail, N. Y., Gerecitano, J. F., Shields, A. F., Unger, T. J., Saint‐Martin, J., Carlson, R. O., Landesman, Y., McCauley, D., et al. (2016) · Journal of Clinical Oncology · doi:10.1200/jco.2015.65.3949 · Cited by 243
Self-citationEtchin, J., Sanda, T., Mansour, M. R., Kentsis, A., Montero, J., Le, B. T., Christie, A. L., McCauley, D., Rodig, S. J., Kauffman, M. G., et al. (2013) · British Journal of Haematology · doi:10.1111/bjh.12231 · Cited by 182
Kim, H. S., Mendiratta, S., Kim, J., Pecot, C. V., Larsen, J. E., Zubovych, I., Seo, B. Y., Kim, J., Eskiocak, B., Chung, H., et al. (2013) · Cell · doi:10.1016/j.cell.2013.09.041 · Cited by 172
Self-citationHER Family Receptor Abnormalities in Lung Cancer Brain Metastases and Corresponding Primary Tumors
Sun, M., Behrens, C., Feng, L., Ozburn, N. C., Tang, X., Yin, G., Komaki, R. U., Varella‐Garcia, M., Hong, W. K., Aldape, K., et al. (2009) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-08-2921 · Cited by 152
Self-citationNeggers, J. E., Vercruysse, T., Jacquemyn, M., Vanstreels, E., Baloglu, E., Shacham, S., Crochiere, M. L., Landesman, Y., & Daelemans, D. (2015) · Chemistry & Biology · doi:10.1016/j.chembiol.2014.11.015 · Cited by 139
Self-citationCheng, Y., Holloway, M. P., Nguyen, K., McCauley, D., Landesman, Y., Kauffman, M. G., Shacham, S., & Altura, R. A. (2014) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-13-0416 · Cited by 105
Self-citationWuerzberger‐Davis, S. M., Chen, Y., Yang, D. T., Kearns, J. D., Bates, P. W., Lynch, C., Ladell, N. C., Yu, M., Podd, A., Zeng, H., et al. (2011) · Immunity · doi:10.1016/j.immuni.2011.01.014 · Cited by 61
IKK is a therapeutic target in KRAS-induced lung cancer with disrupted p53 activity
Bassères, D. S. D. S., Ebbs, A., Cogswell, P. C., & Baldwin, A. S. (2014) · Genes & Cancer · doi:10.18632/genesandcancer.5 · Cited by 35
Brůčková, L., Soukup, T., Víšek, B., Moos, J., Moosová, M., Pavelkova, J., Rezabek, K., Kučerová, L., Mičuda, S., Doleželová, E., et al. (2011) · Journal of Assisted Reproduction and Genetics · doi:10.1007/s10815-011-9617-6 · Cited by 24
siMacro: A Fast and Easy Data Processing Tool for Cell-Based Genomewide siRNA Screens
Singh, N. K., Seo, B. Y., Vidyasagar, M., White, M. A., & Kim, H. S. (2013) · Genomics & Informatics · doi:10.5808/gi.2013.11.1.55 · Cited by 9
Self-citation
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Simanshu, D. K., Nissley, D. V., & McCormick, F. (2017) · Cell · doi:10.1016/j.cell.2017.06.009 · Cited by 1,943
Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy
Skoulidis, F., & Heymach, J. V. (2019) · Nature Reviews Cancer · doi:10.1038/s41568-019-0179-8 · Cited by 1,019
McDonald, E. R., de Weck, A., Schlabach, M. R., Billy, E., Mavrakis, K. J., Hoffman, G. R., Belur, D., Castelletti, D., Frias, E., Gampa, K., et al. (2017) · Cell · doi:10.1016/j.cell.2017.07.005 · Cited by 658
KRAS oncogene in non-small cell lung cancer: clinical perspectives on the treatment of an old target
Román, M., Baraibar, I., López, I., Nadal, E., Rolfo, C., Vicent, S., & Gil-Bazo, I. (2018) · Molecular Cancer · doi:10.1186/s12943-018-0789-x · Cited by 301
KRAS Dimerization Impacts MEK Inhibitor Sensitivity and Oncogenic Activity of Mutant KRAS
Ambrogio, C., Köhler, J., Zhou, Z.-W., Wang, H., Paranal, R., Li, J., Capelletti, M., Caffarra, C., Li, S., Lv, Q., et al. (2018) · Cell · doi:10.1016/j.cell.2017.12.020 · Cited by 270
Metadata
- Authors
- Kim, J., McMillan, E., Kim, H. S., Venkateswaran, N., Makkar, G., Rodriguez-Canales, J., Villalobos, P., Neggers, J. E., Mendiratta, S., Wei, S., Landesman, Y., Senapedis, W., Baloglu, E., Chow, C.-W. B., Frink, R. E., Gao, B., Roth, M., Minna, J. D., Daelemans, D., Wistuba, I. I., Posner, B. A., Scaglioni, P. P., & White, M. A.
- Affiliations
- Yonsei University (KR)
- The University of Texas MD Anderson Cancer Center (US)
- KU Leuven (BE)
- Karyopharm Therapeutics (United States) (US)
- Corresponding author
- White, Michael A.
- ORCID
- Venue
- Nature
- Published
- 2016-09-28
- Volume
- 538
- Issue
- 7623
- Pages
- 114-117
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC5161658
- OpenAlex
- W2526506448
- Cited by
- 202
- References
- 36
- Citations by year
- 2026: 6 · 2025: 11 · 2024: 22 · 2023: 13 · 2022: 23 · 2021: 18 · 2020: 27 · 2019: 23 · 2018: 32 · 2017: 25 · 2016: 1
- FWCI
- 14.04
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- YUHSpace (Yonsei University Medical Library) (submittedVersion, cc-by-nc-nd)
- RePEc: Research Papers in Economics (submittedVersion)
- Lirias (KU Leuven) (submittedVersion)
- Funders
- Cancer Prevention and Research Institute of Texas
- National Cancer Institute (P50CA070907, U01CA176284, RC2CA148225)
- National Institute of General Medical Sciences (T32GM008203)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Structure and Function
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- CRM1, nuclear export, KRAS-mutant lung cancer, non-small cell lung cancer, synthetic lethality, NF-κB, IκBα, YAP, Hippo signaling pathway, verteporfin, drug resistance, RNAi screen, cell lines, KRAS inhibitors
- MeSH terms
- NF-KappaB Inhibitor alpha, Verteporfin, Hippo Signaling Pathway, YAP-Signaling Proteins, TEA Domain Transcription Factors, Exportin 1 Protein, Animals, Carcinoma, Non-Small-Cell Lung, Cell Nucleus, Cell Survival, DNA-Binding Proteins, Female, Genes, Lethal, Humans, Lung Neoplasms, Mutation, Nuclear Proteins, Phosphoproteins, Porphyrins, Transcription Factors, Signal Transduction, Proto-Oncogene Proteins p21(ras), NF-kappa B, Protein Serine-Threonine Kinases, Receptors, Cytoplasmic and Nuclear, Active Transport, Cell Nucleus, Xenograft Model Antitumor Assays, Karyopherins, RNA Interference, RNA, Small Interfering, Follistatin-Related Proteins, Cell Line, Tumor, Adaptor Proteins, Signal Transducing, Cell Proliferation, Mice
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