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A murine lung cancer co-clinical trial identifies genetic modifiers of therapeutic response
Open accessAbstract
Targeted therapies have demonstrated efficacy against specific subsets of molecularly defined cancers. Although most patients with lung cancer are stratified according to a single oncogenic driver, cancers harbouring identical activating genetic mutations show large variations in their responses to the same targeted therapy. The biology underlying this heterogeneity is not well understood, and the impact of co-existing genetic mutations, especially the loss of tumour suppressors, has not been fully explored. Here we use genetically engineered mouse models to conduct a 'co-clinical' trial that mirrors an ongoing human clinical trial in patients with KRAS-mutant lung cancers. This trial aims to determine if the MEK inhibitor selumetinib (AZD6244) increases the efficacy of docetaxel, a standard of care chemotherapy. Our studies demonstrate that concomitant loss of either p53 (also known as Tp53) or Lkb1 (also known as Stk11), two clinically relevant tumour suppressors, markedly impaired the response of Kras-mutant cancers to docetaxel monotherapy. We observed that the addition of selumetinib provided substantial benefit for mice with lung cancer caused by Kras and Kras and p53 mutations, but mice with Kras and Lkb1 mutations had primary resistance to this combination therapy. Pharmacodynamic studies, including positron-emission tomography (PET) and computed tomography (CT), identified biological markers in mice and patients that provide a rationale for the differential efficacy of these therapies in the different genotypes. These co-clinical results identify predictive genetic biomarkers that should be validated by interrogating samples from patients enrolled on the concurrent clinical trial. These studies also highlight the rationale for synchronous co-clinical trials, not only to anticipate the results of ongoing human clinical trials, but also to generate clinically relevant hypotheses that can inform the analysis and design of human studies.
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“LKB1 deficiency by immunohistochemistry is associated with lack of benefit from the addition of the vascular endothelial growth factor A (VEGFA) inhibitor bevacizumab to platinum doublet chemotherapy163, 164.”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [164]
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Cites
Gefitinib or Carboplatin–Paclitaxel in Pulmonary Adenocarcinoma
Mok, T. S., Wu, Y.-L., Thongprasert, S., Yang, C.-H., Chu, D.-T., Saijo, N., Sunpaweravong, P., Han, B., Margono, B., Ichinose, Y., et al. (2009) · New England Journal of Medicine · doi:10.1056/nejmoa0810699 · Cited by 8,261
Gefitinib or Chemotherapy for Non–Small-Cell Lung Cancer with Mutated EGFR
Maemondo, M., Inoue, A., Kobayashi, K., Sugawara, S., Oizumi, S., Isobe, H., Gemma, A., Harada, M., Yoshizawa, H., Kinoshita, I., et al. (2010) · New England Journal of Medicine · doi:10.1056/nejmoa0909530 · Cited by 5,525
Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors
Demetri, G. D., von Mehren, M., Blanke, C. D., Van den Abbeele, A. D., Eisenberg, B., Roberts, P. J., Heinrich, M. C., Tuveson, D. A., Singer, S., Janicek, M., et al. (2002) · New England Journal of Medicine · doi:10.1056/nejmoa020461 · Cited by 4,389
Self-citationUse of all-trans retinoic acid in the treatment of acute promyelocytic leukemia
Huang, M., Ye, Y., Chen, S. R., Chai, J., Lu, J., Zhoa, L., Gu, L.-J., & Wang, Z.-Y. (1988) · Blood · doi:10.1182/blood.v72.2.567.567 · Cited by 2,445
Nagata, Y., Lan, K.-H., Zhou, X., Tan, M., Esteva, F. J., Sahin, A. A., Klos, K. S., Li, P., Monia, B. P., Nguyen, N. T., et al. (2004) · Cancer Cell · doi:10.1016/j.ccr.2004.06.022 · Cited by 1,858
Engelman, J. A., Chen, L., Tan, X., Crosby, K., Guimaraes, A. R., Upadhyay, R., Maira, M., McNamara, K., Perera, S. A., Song, Y., et al. (2008) · Nature Medicine · doi:10.1038/nm.1890 · Cited by 1,330
Self-citationCharacterizing the cancer genome in lung adenocarcinoma
Weir, B. A., Woo, M. S., Getz, G., Perner, S., Ding, L., Beroukhim, R., Lin, W. M., Province, M. A., Kraja, A., Johnson, L. A., et al. (2007) · Nature · doi:10.1038/nature06358 · Cited by 1,105
Self-citationLKB1 modulates lung cancer differentiation and metastasis
Ji, H., Ramsey, M. R., Hayes, D. N., Fan, C., McNamara, K., Kozlowski, P., Torrice, C., Wu, M. C., Shimamura, T., Perera, S. A., et al. (2007) · Nature · doi:10.1038/nature06030 · Cited by 1,064
Self-citationMascaux, C., Iannino, N., Martin, B., Paesmans, M., Berghmans, T., Dusart, M., Haller, A., Lothaire, P., Meert, A.-P., Noël, S., et al. (2004) · British Journal of Cancer · doi:10.1038/sj.bjc.6602258 · Cited by 615
Yeh, T. C., Marsh, V., Bernat, B. A., Ballard, J., Colwell, H., Evans, R. J., Parry, J., Smith, D. J., Brandhuber, B. J., Gross, S. D., et al. (2007) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-06-1150 · Cited by 578
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Items 201–300 of 446
Use of big data in drug development for precision medicine
Kim, R. S., Goossens, N., & Hoshida, Y. (2016) · Expert Review of Precision Medicine and Drug Development · doi:10.1080/23808993.2016.1174062 · Cited by 36
“Co-clinical trial, simultaneously assessing therapeutic effect in human and mechanisms in animal model, was also proposed [34].”
BackgroundHuman pharmacogenetic analysis in chimeric mice with ‘humanized livers’
Hu, Y., Wu, M., Nishimura, T., Zheng, M., & Peltz, G. (2012) · Pharmacogenetics and Genomics · doi:10.1097/fpc.0b013e32835cb2c7 · Cited by 36
Genetically engineered mouse models of PI3K signaling in breast cancer
Klarenbeek, S., van Miltenburg, M. H., & Jonkers, J. (2013) · Molecular Oncology · doi:10.1016/j.molonc.2013.02.003 · Cited by 36
Evaluation of the Genisys4, a Bench-Top Preclinical PET Scanner
Herrmann, K., Dahlbom, M. L., Nathanson, D. A., Liu, W., Radu, C. G., Chatziioannou, A. F., & Czernin, J. G. (2013) · Journal of Nuclear Medicine · doi:10.2967/jnumed.112.114926 · Cited by 35
“These applications have generated considerable interest among tumor biologists (9), who have traditionally used optical imaging approaches for noninvasive preclinical imaging (10).”
BackgroundMethodFang, B. (2015) · Acta Biochimica et Biophysica Sinica · doi:10.1093/abbs/gmv090 · Cited by 37
“A study comparing treatment responses of Kras-driven lung cancer with concomitant loss of either Tp53 or Stk11 revealed that loss of either gene markedly impaired the response of Kras mutant cancers to docetaxel monotherapy [96].”
The Molecular Pathology of Lung Cancer
Sholl, L. M. (2016) · Surgical pathology clinics · doi:10.1016/j.path.2016.04.003 · Cited by 36
He, Q., Li, J., Dong, F., Cai, C., & Zou, X. (2017) · Molecular Medicine Reports · doi:10.3892/mmr.2017.6852 · Cited by 35
Self-citationERK Inhibitor LY3214996-Based Treatment Strategies forRAS-Driven Lung Cancer
Köhler, J., Zhao, Y., Li, J., Gokhale, P. C., Tiv, H. L., Knott, A., Wilkens, M. K., Soroko, K. M., Lin, M., Ambrogio, C., et al. (2021) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-20-0531 · Cited by 36
“3G) may hold promise for this drug combination also in these otherwise hard to treat lung cancer subtypes (47, 54).”
BackgroundSelf-citationOptimal therapy for concomitant EGFR and TP53 mutated non-small cell lung cancer: a real-world study
Sun, H., Ren, P., Chen, Y., Lan, L., Yan, Z., Yang, Y., Wang, B., Wang, C., Li, Y., Li, L., et al. (2023) · BMC Cancer · doi:10.1186/s12885-023-10637-4 · Cited by 36
“The complete loss of TP53 function can accelerate the transformation potential of driver oncogenes in lung cancers [19].”
BackgroundSynergy of WEE1 and mTOR Inhibition in Mutant KRAS -Driven Lung Cancers
Hai, J., Liu, S., Bufe, L. E., Do, K. T., Chen, T., Wang, X., Ng, C., Li, S., Tsao, M., Shapiro, G. I., et al. (2017) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-17-1098 · Cited by 36
“We and others have demonstrated that KRAS/LKB1-mutant NSCLCs represent a genetically and functionally distinct subset of NSCLC (8).”
BackgroundInfluentialSelf-citationLiu, Y., Li, Y., Wang, X., Liu, F., Gao, P., Quinn, M. M., Li, F., Merlino, A. A., Benes, C., Liu, Q., et al. (2017) · Cancer Research · doi:10.1158/0008-5472.can-17-0567 · Cited by 33
“We thank Dr. Yuchuan Wang for 18 F-FDG-PET/CT image study.”
Self-citationStrategies for derisking translational processes for biomedical technologies
Abou-El-Enein, M., Duda, G. N., Gruskin, E. A., & Grainger, D. W. (2017) · Trends in Biotechnology · doi:10.1016/j.tibtech.2016.07.007 · Cited by 36
Lung cancer biomarkers, targeted therapies and clinical assays.
Patel, J. N., Ersek, J. L., & Kim, E. S. (2015) · PubMed · doi:10.3978/j.issn.2218-6751.2015.06.02 · Cited by 34
“In a preclinical study, KRAS mutated mice (also mutated for STK11 and TP53) were treated with docetaxel alone or with an investigational MEK inhibitor, selumetinib (58).”
MethodGenomic profiling toward precision medicine in non-small cell lung cancer: getting beyond EGFR
Whitsett, T. G., Richer, A. L., Friel, J. M., Carson, V. M., & Inge, L. J. (2015) · Pharmacogenomics and Personalized Medicine · doi:10.2147/pgpm.s52845 · Cited by 35
Selumetinib for the treatment of non-small cell lung cancer
Casaluce, F., Sgambato, A., Maione, P., Sacco, P. C., Santabarbara, G., & Gridelli, C. (2017) · Expert Opinion on Investigational Drugs · doi:10.1080/13543784.2017.1351543 · Cited by 33
“Results of additional preclinical in vivo studies have shown that the combination of selumetinib and docetaxel leads to greater tumor growth inhibition or regression and apoptosis [47,48].”
BackgroundKushwaha, D. S., O’Leary, C., Cron, K. R., Deraska, P. V., Zhu, K., D’Andrea, A. D., & Kozono, D. (2015) · Cancer Biology & Therapy · doi:10.1080/15384047.2014.1002358 · Cited by 32
“irradiation of A549 or NCIH460 cells with single 20 Gy fractions, yield rates of apoptosis of only 5–35%.(14) Following USP9X inhibition, however, we observed 2- to 3-fold increases in apoptosis.”
BackgroundChand, H. S., Montano, G., Huang, X., Randell, S. H., Mebratu, Y. A., Petersen, H. V., & Tesfaigzi, Y. (2014) · Nature Communications · doi:10.1038/ncomms6567 · Cited by 33
KRAS-Mutant Non-Small-Cell Lung Cancer: From Past Efforts to Future Challenges
Ceddia, S., Landi, L. M., & Cappuzzo, F. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23169391 · Cited by 35
“The addition of selumetinib improved results in mice with KRAS-mutant cancers and TP53 co-mutations, while those with KRAS and STK11 co-mutations developed primary resistance to this combination therapy [37].”
BackgroundSorafenib in non-small cell lung cancer
Zhang, J. J., Gold, K. A., & Kim, E. (2012) · Expert Opinion on Investigational Drugs · doi:10.1517/13543784.2012.699039 · Cited by 32
Shackelford, D. B. (2013) · Journal of Carcinogenesis · doi:10.4103/1477-3163.116323 · Cited by 31
“[48,49] LKB1 mediated regulation of mitochondrial homeostasis Recent work in HSCs and NSCLC has shed light on LKB1 role as a regulator of mitochondrial function and aerobic metabolism, where LKB1 ‑/‑ murine HSCs show mitochondrial defects including increased mitochondrial content and reduced…”
Janne, P. A., Mann, H., & Ghiorghiu, D. C. (2015) · Clinical Lung Cancer · doi:10.1016/j.cllc.2015.12.010 · Cited by 31
Role of INSL4 Signaling in Sustaining the Growth and Viability of LKB1-Inactivated Lung Cancer
Yang, R., Li, S. W., Chen, Z., Zhou, X., Wei Min, N. I., Fu, D., Lu, J., Kaye, F. J., & Wu, L. (2018) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/djy166 · Cited by 28
Self-citationKaufman, J. M., Yamada, T., Park, K., Timmers, C. D., Amann, J. M., & Carbone, D. P. (2016) · Cancer Research · doi:10.1158/0008-5472.can-16-1639 · Cited by 31
Azaro, A., Rodon, J. A., Calles, A., Braña, I., Hidalgo, M. M., Lopez-Casas, P. P., Muñoz, M., Westwood, P., Miller, J. A., Moser, B. A., et al. (2015) · Investigational New Drugs · doi:10.1007/s10637-015-0241-7 · Cited by 35
Epigenetic CRISPR Screens Identify Npm1 as a Therapeutic Vulnerability in Non–Small Cell Lung Cancer
Li, F., Ng, W., Luster, T. A., Hu, H., Sviderskiy, V. O., Dowling, C. M., Hollinshead, K. E. R., Zouitine, P., Zhang, H., Huang, Q., et al. (2020) · Cancer Research · doi:10.1158/0008-5472.can-19-3782 · Cited by 29
“Tumor volume within the whole lung was quantified using 3D slicer software to reconstruct MRI volumetric measurements as described previously (12).”
MethodSelf-citationMolecular Pathways: The Basis for Rational Combination Using MEK Inhibitors in KRAS-Mutant Cancers
Okumura, S., & Janne, P. A. (2014) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-13-2365 · Cited by 30
Pyo, K., Lim, S. M., Kim, H. R., Sung, Y. H., Yun, M. R., Kim, S., Kim, H., Kang, H. N., Lee, J. M., Kim, S. G., et al. (2016) · Journal of Thoracic Oncology · doi:10.1016/j.jtho.2016.10.022 · Cited by 30
“GEMMs allow murine clinical trials that can predict the outcome of clinical trials and accelerate more effective oncologic drug development.(19) In addition, it is easier to identify mechanisms of resistance in murine models than in real patients, which may facilitate discovery of rational combinatorial strategies tha…”
BackgroundMouse tumour models to guide drug development and identify resistance mechanisms
Thakur, M. D., Pryer, N., & Singh, M. (2013) · The Journal of Pathology · doi:10.1002/path.4285 · Cited by 30
“Mutant kras-driven GEMMs of NSCLC were more recently shown to parallel clinical outcomes with chemotherapy and a targeted MEK inhibitor in a new paradigm termed a ‘co-clinical’ trial, wherein the preclinical experiments were conducted at the same time as an ongoing clinical trial [38].”
ResultKRAS-Mutant Lung Cancers in the Era of Targeted Therapy
Naidoo, J., & Drilon, A. E. D. C. (2015) · Advances in experimental medicine and biology · doi:10.1007/978-3-319-24223-1_8 · Cited by 33
Şahin, Ö., Wang, Q., Brady, S. W., Ellis, K., Wang, H., Chang, C., Zhang, Q., Priya, P., Zhu, R., Wong, S. T. C., et al. (2014) · Cell Research · doi:10.1038/cr.2014.37 · 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
Zheng, C. J., Li, X., Ren, Y., Yin, Z., & Zhou, B. (2020) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2020.00030 · Cited by 28
“Patients harboring activated EGFR or KRAS mutation were mostly defined as 2 non-overlapping subgroups at the molecular level, showing large diversity in response to the same tyrosine kinase inhibitor (TKI) therapy (Chen et al., 2012).”
BackgroundVelasco, M. A. D., Kura, Y., Yoshikawa, K., Nishio, K., Davies, B. R., & Uemura, H. (2016) · Oncotarget · doi:10.18632/oncotarget.7557 · Cited by 28
“Other investigators have already applied this in KRAS mutant mouse models of non-smallcell lung carcinoma and pancreatic adenocarcinoma and in mouse “co-clinical trials” [41-45].”
MethodA Sensitive NanoString-Based Assay to Score STK11 (LKB1) Pathway Disruption in Lung Adenocarcinoma
Chen, L., Engel, B. E., Welsh, E. A., Yoder, S., Brantley, S. G., Chen, D., Beg, A. A., Cao, C., Kaye, F. J., Haura, E. B., et al. (2016) · Journal of Thoracic Oncology · doi:10.1016/j.jtho.2016.02.009 · Cited by 28
Wang, P., Yang, W. Z., Guo, H., Dong, H., Guo, Y., Gan, H., Wang, Z., Cheng, Y., Deng, Y., Xie, S.-Z., et al. (2021) · Advanced Science · doi:10.1002/advs.202101501 · Cited by 26
Tumor Organoid and Spheroid Models for Cervical Cancer
Kutle, I., Polten, R., Hachenberg, J., Klapdor, R., Morgan, M. A., & Schambach, A. (2023) · Cancers · doi:10.3390/cancers15092518 · Cited by 28
“Other important weaknesses include the inability to monitor cellular responses to therapeutic challenges in real time, challenges to predict tumor formation, high costs, high hands-on time requirements, and increased ethical concerns [31].”
BackgroundPreclinical Models for the Study of Lung Cancer Pathogenesis and Therapy DevelopmentPreprint
Estape, A. A., Foggetti, G., Starrett, J. H., Nguyen, D. X., & Politi, K. A. (2021) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a037820 · Cited by 23
Gene-expression data integration to squamous cell lung cancer subtypes reveals drug sensitivity
Wu, D., Pang, Y., Wilkerson, M. D., Wang, D., Hammerman, P. S., & Liu, J. S. (2013) · British Journal of Cancer · doi:10.1038/bjc.2013.452 · Cited by 25
“These studies have not yet clearly identified a cell-of-origin for SqCCs but have correlated lung SqCC expression subtypes with specific time points in lung development in the mouse (Mariani et al, 2002; Chen et al, 2012).”
BackgroundSelf-citationNärhi, K. M., Nagaraj, A. S., Parri, E., Turkki, R., van Duijn, P. W., Hemmes, A., Lahtela, J., Uotinen, V., Mäyränpää, M. I., Salmenkivi, K., et al. (2018) · The Journal of Pathology · doi:10.1002/path.5059 · Cited by 23
“We chose three compounds with reported efficacy in preclinical studies on Kras-driven NSCLC [14,25], namely the dual PI3K and mTOR inhibitor NVP-BEZ235 or dact, the MEK inhibitor AZD6244 or sel, and the SRC inhibitor sar (Figure 3A).”
BackgroundSelumetinib-based therapy in uveal melanoma patient-derived xenografts
Decaudin, D., Botty, R. E., Diallo, B., Massonnet, G., Fleury, J., Naguez, A., Raymondie, C., Davies, E. J., Smith, A., Wilson, J., et al. (2018) · Oncotarget · doi:10.18632/oncotarget.24670 · Cited by 25
“One of the key challenges in translational research is the development of relevant preclinical models for the testing of clinical concepts, in so-called ‘co-clinical’ trials [18].”
Lopes, E. C., Sawant, A., Moore, D. F., Ke, H., Shi, F., Laddha, S. V., Chen, Y., Sharma, A., Naumann, J., Guo, J. Y., et al. (2023) · Clinical and Translational Medicine · doi:10.1002/ctm2.1298 · Cited by 26
Ma, T., Galimberti, F., Erkmen, C. P., Memoli, V. A., Chinyengetere, F., Sempere, L. F., Beumer, J. H., Anyang, B. N., Nugent, W. C., Johnstone, D. W., et al. (2013) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-12-0933 · Cited by 23
“This coclinical trial approach extends prior work (42, 43).”
MethodLKB1 inactivation sensitizes non-small cell lung cancer to pharmacological aggravation of ER stress
Inge, L. J., Friel, J. M., Richer, A. L., Fowler, A. J., Whitsett, T. G., Smith, M. A., Tran, N. L., & Bremner, R. M. (2014) · Cancer Letters · doi:10.1016/j.canlet.2014.06.011 · Cited by 25
Gregorc, V., Lazzari, C., Mandalà, M., Ippati, S., Bulotta, A., Cangi, M. G., Khater, A., Viganò, M. G., Mirabile, A., Pecciarini, L., et al. (2021) · Cancers · doi:10.3390/cancers13092023 · Cited by 25
“Docetaxel alone or in combination with the MEK inhibitor selumetinib [26] resulted in lower efficacy in KRAS mutant mice harboring LKB1 or TP53 mutations, compared with those carrying KRAS mutations only.”
BackgroundPatient-derived tumor xenograft models for melanoma drug discovery
Harris, A. L., Joseph, R. W., & Copland, J. A. (2016) · Expert Opinion on Drug Discovery · doi:10.1080/17460441.2016.1216968 · Cited by 23
Li, Y., Wu, Y., Xia, Q., Zhao, Y., Zhao, R., & Deng, S. (2019) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2019.109496 · Cited by 23
Rao, S. R., Somarelli, J. A., Altunel, E., Selmic, L. E., Byrum, M., Sheth, M. U., Cheng, S., Ware, K. E., Kim, S. Y., Prinz, J. A., et al. (2020) · Frontiers in Oncology · doi:10.3389/fonc.2020.00117 · Cited by 21
“These patient-derived models are also being used to develop personalized treatments and guide development of novel targeted agents (6, 7).”
BackgroundYang, Z., Chen, Y., Wang, Y., Wang, S., Hu, M., Zhang, B., & Han, B. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2021.681429 · Cited by 22
“The complete loss of TP53 function, mainly manifested as single-base substitution and loss of alleles, can catalyze the transformation potential of oncogene drivers in lung cancer and inhibit tumor response to chemotherapy, radiotherapy and EGFR-TKIs (15, 16).”
BackgroundSelf-citationKRAS mutant NSCLC, a new opportunity for the synthetic lethality therapeutic approach.
de Castro, J., & Belda-Iniesta, C. (2013) · Europe PMC (PubMed Central) · doi:10.3978/j.issn.2218-6751.2013.02.07 · Cited by 22
Porcine model elucidates function of p53 isoform in carcinogenesis and reveals novel circTP53 RNA
Niu, G., Hellmuth, I., Flisikowska, T., Pausch, H., Rieblinger, B., Carrapeiro, A. R., Schade, B., Böhm, B., Kappe, E., Fischer, K., et al. (2021) · Oncogene · doi:10.1038/s41388-021-01686-9 · Cited by 22
Quantitative In Vivo Analyses Reveal a Complex Pharmacogenomic Landscape in Lung Adenocarcinoma
Li, C., Lin, W.-Y., Rizvi, H. A., Cai, H., McFarland, C. D., Rogers, Z. N., Yousefi, M., Winters, I. P., Rudin, C. M., Petrov, D. A., et al. (2021) · Cancer Research · doi:10.1158/0008-5472.can-21-0716 · Cited by 22
“Despite the potential value of these models in preclinical translation 87 studies, the breadth of their utility has been limited in practice by the fact that they are neither 88 readily scalable nor sufficiently quantitative(23-27).”
BackgroundLKB1 drives stasis and C/EBP-mediated reprogramming to an alveolar type II fate in lung cancer
Murray, C. W., Brady, J. J., Han, M., Cai, H., Tsai, M. K., Pierce, S. E., Cheng, R., Demeter, J., Feldser, D. M., Jackson, P. K., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-28619-8 · Cited by 22
Individual nodule tracking in micro-CT images of a longitudinal lung cancer mouse model
Rudyanto, R. D., Bastarrika, G., de Biurrun, G., Agorreta, J., Montuenga, L. M., Ortíz-de-Solórzano, C., & Muñoz‐Barrutia, A. (2013) · Medical Image Analysis · doi:10.1016/j.media.2013.07.002 · Cited by 22
Desai, A., Menon, S. P., & Dy, G. K. (2016) · PubMed Central · doi:10.28092/j.issn.2095-3941.2016.0008 · Cited by 22
A high-content cellular senescence screen identifies candidate tumor suppressors, including EPHA3
Lahtela, J., Corson, L. B., Hemmes, A., Brauer, M. J., Koopal, S., Lee, J., Hunsaker, T. L., Jackson, P. K., & Verschuren, E. W. (2013) · Cell Cycle · doi:10.4161/cc.23515 · Cited by 20
Froesch, P., Mark, M. T., Rothschild, S. I., Li, Q., Godar, G., Rusterholz, C., Leibundgut, E. O., Schmid, S., Colombo, I., Metaxas, Y., et al. (2021) · Lung Cancer · doi:10.1016/j.lungcan.2021.04.002 · Cited by 20
Gadgeel, S. M., Miao, J., Riess, J. W., Moon, J., Mack, P. C., Gerstner, G. J., Burns, T. F., Taj, A., Akerley, W., Dragnev, K. H., et al. (2023) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-22-3947 · Cited by 22
In Vivo Imaging of Multidrug Resistance Using a Third Generation MDR1 Inhibitor
Sprachman, M. M., Laughney, A. M., Köhler, R. H., & Weissleder, R. (2014) · Bioconjugate Chemistry · doi:10.1021/bc500154c · Cited by 21
Larráyoz, M., Pı́o, R., Pajares, M. J., Zudaire, I., Ajona, D., Casanovas, O., Montuenga, L. M., & Agorreta, J. (2014) · EMBO Molecular Medicine · doi:10.1002/emmm.201303214 · Cited by 21
“In addition, mouse models can be used simultaneously to human clinical trials following the rationale of co-clinical trials (Chen et al , 2012).”
InfluentialKRAS-driven lung adenocarcinoma: combined DDR1/Notch inhibition as an effective therapy
Ambrogio, C., Nadal, E., Villanueva, A., Goméz-López, G., Cash, T. P., Barbacid, M., & Santamarı́a, D. (2016) · ESMO Open · doi:10.1136/esmoopen-2016-000076 · Cited by 21
“However, tumours with mutated Kras and Lkb1 loss did not benefit from the addition of selumetinib to docetaxel.(13) In a phase II clinical trial on patients with lung cancer, selumetinib plus docetaxel significantly improved progressionfree survival in patients with KRAS-mutant lung adenocarcinoma resulting in a trend”
BackgroundSelumetinib in the Treatment of Non-Small-Cell Lung Cancer
Bernabé, R., Patrão, A. S., Carter, L., Blackhall, F. H., & Dean, E. J. (2016) · Future Oncology · doi:10.2217/fon-2016-0132 · Cited by 21
Farnsworth, D., Inoue, Y., Johnson, F. D., de Rappard-Yuswack, G., Lu, D., Shi, R., Ma, L. I. J., Mattar, M. S., Somwar, R., Ladanyi, M., et al. (2022) · npj Precision Oncology · doi:10.1038/s41698-022-00328-x · Cited by 21
Ndembe, G., Intini, I., Moro, M., Grasselli, C., Panfili, A., Panini, N., Bleve, A., Occhipinti, M. A., Borzi, C., Garassino, M. C., et al. (2024) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-023-02933-5 · Cited by 22
“However, the heterogeneity of this pathology means that a substantial subgroup of patients does not benefit from the current treatment lines [10, 11].”
BackgroundBlocker, S. J., Mowery, Y. M., Holbrook, M., Qi, Y. P., Kirsch, D. G., Johnson, G. A., & Badea, C. T. (2019) · PLoS ONE · doi:10.1371/journal.pone.0207555 · Cited by 20
Targeting KRAS-mutant non-small cell lung cancer: challenges and opportunities
Zhang, J., Park, D., Shin, D. M., & Deng, X. (2015) · Acta Biochimica et Biophysica Sinica · doi:10.1093/abbs/gmv118 · Cited by 20
Dependency of human and murine LKB1-inactivated lung cancer on aberrant CRTC-CREB activation
Zhou, X., Li, J. W., Chen, Z., Wei Min, N. I., Li, X., Yang, R., Shen, H., Liu, J., DeMayo, F. J., Lu, J., et al. (2021) · eLife · doi:10.7554/elife.66095 · Cited by 18
“…deficiency exhibits resistance to chemotherapy, targeted therapeutics and especially to immune checkpoint inhibitors in preclinical models and/or human patients ( Chen et al., 2012 ; Carretero et al., 2010 ; Han et al., 2014 ; Skoulidis et al., 2018 ; Schabath et al., 2016 ; Rizvi et al., 2018 ).”
Self-citationSelumetinib: A Promising Pharmacologic Approach for KRAS -Mutant Advanced Non-Small-Cell Lung Cancer
Metro, G., Chiari, R., Baldi, A., Angelis, V. D., Minotti, V., & Crinò, L. (2013) · Future Oncology · doi:10.2217/fon.12.198 · Cited by 19
“To this regard, in a genetically engineered mouse model with KRAS‐mutant lung cancers, it was shown that concomitant loss of either p53 or LKB1 markedly impaired the response of KRAS‐mutant cancers to docetaxel monotherapy, but the addition of selumetinib provided substantial benefit for mice with lung cancer caused b…”
BackgroundFN14 expression correlates with MET in NSCLC and promotes MET-driven cell invasion
Whitsett, T. G., Ensign, S. P. F., Dhruv, H., Inge, L. J., Kurywchak, P. A., Wolf, K. K., Lobello, J. R., Kingsley, C. B., Allen, J. W., Weiss, G. J., et al. (2014) · Clinical & Experimental Metastasis · doi:10.1007/s10585-014-9653-6 · Cited by 19
“Transient expression of Cre and subsequent expression of KRAS and homozygous deletion of LKB1 within the lungs of the KRAS/LKB1 mice results in multi-focal, highly aggressive NSCLC with both local and distant metastases [25, 26].”
BackgroundFrom mice to men: GEMMs as trial patients for new NSCLC therapies
Hayes, S. A., Hudson, A. L., Clarke, S. J., Molloy, M. P., & Howell, V. M. (2014) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2014.04.002 · Cited by 19
Ebi, H., Faber, A. C., Engelman, J. A., & Yano, S. (2014) · Cancer Science · doi:10.1111/cas.12383 · Cited by 18
Self-citationIn vitro clinical trials: the future of cell-based profiling
Ross, N. T., & Wilson, C. J. (2014) · Frontiers in Pharmacology · doi:10.3389/fphar.2014.00121 · Cited by 20
“In a successful example, Chen et al. (2012) have tested the use of the MEK inhibitor selumetinib in combination with docetaxel in a KRAS-mutant lung cancer trial.”
MethodSOX9 dependent FOXA1 expression promotes tumorigenesis in lung carcinoma
Wang, X., Yin, Y., & Du, R. (2019) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2019.05.169 · Cited by 19
Translational research: A patient-centered approach to bridge the valley of death
Thomas, A., Desai, P. A., & Takahashi, N. (2022) · Cancer Cell · doi:10.1016/j.ccell.2022.04.014 · Cited by 18
The LKB1 Tumor Suppressor as a Biomarker in Mouse and Human Tissues
Nakada, Y., Stewart, T. G., Peña, C. G., Zhang, S., Zhao, N., Bardeesy, N. M., Sharpless, N. E., Wong, K., Hayes, D. N., & Castrillón, D. H. (2013) · PLoS ONE · doi:10.1371/journal.pone.0073449 · Cited by 19
Self-citationMutation of TP53 and Alteration of p14arf Expression in EGFR- and KRAS-Mutated Lung Adenocarcinomas
Cortot, A. B., Younes, M., Martel-Planche, G., Guibert, B., Isaac, S., Souquet, P.-J., Commo, F., Girard, P., Fouret, P. J., Brambilla, E. M., et al. (2013) · Clinical Lung Cancer · doi:10.1016/j.cllc.2013.08.003 · Cited by 18
Fumagalli, C., Vacirca, D., Rappa, A., Passaro, A., Guarize, J., Raviele, P. R., de Marinis, F., Spaggiari, L., Casadio, C., Viale, G., et al. (2018) · Journal of Clinical Pathology · doi:10.1136/jclinpath-2018-205032 · Cited by 18
Blocker, S. J., Holbrook, M., Mowery, Y. M., Sullivan, D. C., & Badea, C. T. (2020) · PLoS ONE · doi:10.1371/journal.pone.0225019 · Cited by 18
Treating non-small cell lung cancer with selumetinib: an up-to-date drug evaluation
Имянитов, Е. Н., Levchenko, E., Kuligina, E. S., & Orlov, S. (2020) · Expert Opinion on Pharmacotherapy · doi:10.1080/14656566.2020.1798930 · Cited by 17
Interplay between p53 and VEGF: how to prevent the guardian from becoming a villain
Haupt, S., Gamell, C., Wolyniec, K., & Haupt, Y. (2013) · Cell Death and Differentiation · doi:10.1038/cdd.2013.51 · Cited by 16
The Cinderella Effect: Searching for the Best Fit between Mouse Models and Human Diseases
Sundberg, J. P., Roopenian, D. C., Liu, E. T., & Schofield, P. N. (2013) · Journal of Investigative Dermatology · doi:10.1038/jid.2013.238 · Cited by 16
“…notable successes for mouse models used in combination with human clinical studies may be found in cancer (Bos et al., 2010; Nardella et al., 2011; Chen et al., 2012; Johnson, 2012; Juvekar et al., 2012) and skin 2 Journal of Investigative Dermatology Mouse Genomes Project - SNPs…”
Abdel-Rahman, O. M. (2016) · Therapeutic Advances in Respiratory Disease · doi:10.1177/1753465816632111 · Cited by 17
“Moreover, a murine lung cancer cotrial conducted concomitantly with a randomized phase II study of docetaxel with or without selumitinib showed that the addition of selumetinib provided substantial benefit for mice with lung cancer caused by KRAS [Chen et al. 2012].”
BackgroundMethodInhibition of non-small cell lung cancer (NSCLC) growth by a novel small molecular inhibitor of EGFR
Li, J., Deng, H., Hu, M., Fang, Y., Vaughn, A., Cai, X., Xu, L., Wan, W., Li, Z., Chen, S., et al. (2015) · Oncotarget · doi:10.18632/oncotarget.3155 · Cited by 16
“Approximately 80% of all lung cancer cases are categorized as non-small cell lung cancer (NSCLC), which is typically diagnosed at advanced stages [2, 3].”
BackgroundSelf-citationKim, E. Y., Kim, A., Kim, S. I., & Chang, Y. S. (2014) · Cancer Letters · doi:10.1016/j.canlet.2014.12.041 · Cited by 16
Frequency and clinical significance of NF1 mutation in lung adenocarcinomas from East Asian patients
Pan, Y., Yuan, C., Cheng, C., Zhang, Y., Ma, Y., Zheng, D., Zheng, S., Li, Y., Jin, Y., Sun, Y., et al. (2018) · International Journal of Cancer · doi:10.1002/ijc.31871 · Cited by 16
Self-citationTreatment of KRAS-Mutant Non–Small Cell Lung Cancer
Kaufman, J. M., & Stinchcombe, T. E. (2017) · JAMA · doi:10.1001/jama.2017.3436 · Cited by 16
Wang, T., Guo, H., Li, Q., Wu, W., Yu, M., Zhang, L., Li, C., Song, J., Wang, Z., Zhang, J., et al. (2022) · Cell Reports · doi:10.1016/j.celrep.2022.111210 · Cited by 15
Hasanzadeh, A., Ebadati, A., Dastanpour, L., Aref, A. R., Zangabad, P. S., Kalbasi, A., Dai, X., Mehta, G., Ghasemi, A., Fatahi, Y., et al. (2023) · ACS Pharmacology & Translational Science · doi:10.1021/acsptsci.3c00102 · Cited by 16
Bağcı, U., Krämer-Marek, G., & Mollura, D. J. (2013) · EJNMMI Research · doi:10.1186/2191-219x-3-49 · Cited by 15
Costa, D. B. (2018) · Annals of Oncology · doi:10.1093/annonc/mdy339 · Cited by 15
Self-citationMouse lung automated segmentation tool for quantifying lung tumors after micro-computed tomography
Montgomery, M. K., David, J., Zhang, H., Ram, S., Deng, S., Premkumar, V., Manzuk, L. K., Jiang, Z. K., & Giddabasappa, A. (2021) · PLoS ONE · doi:10.1371/journal.pone.0252950 · Cited by 15
“Genetically engineered mouse (GEM) models of lung cancer have played important roles in understanding the driver mutations and disease pathology as well as in assessment of novel drug candidates prior to clinical evaluation [8, 9].”
BackgroundOf Model Pets and Cancer Models: An Introduction to Mouse Models of CancerPreprint
Lunardi, A., Nardella, C., Clohessy, J. G., & Pandolfi, P. P. (2013) · Cold Spring Harbor Protocols · doi:10.1101/pdb.top069757 · Cited by 15
“2013); and MEK inhibitor selumetinib provides substantial benefit to Kras/Trp53 but not to Kras/ Lkb1doublenull lung cancermousemodels resistant todocetaxel asmonotherapy (Chen et al. 2012).”
InfluentialSelf-citationThe Potential of Hyperpolarized 13C MRI in Assessing Signaling Pathways in Cancer
Zhang, H. (2014) · Academic Radiology · doi:10.1016/j.acra.2013.11.015 · Cited by 14
Overview of KRAS‐Driven Genetically Engineered Mouse Models of Non‐Small Cell Lung Cancer
Sheridan, C., & Downward, J. (2015) · Current Protocols in Pharmacology · doi:10.1002/0471141755.ph1435s70 · Cited by 14
Co-Clinical Trials: An Innovative Drug Development Platform for Cholangiocarcinoma
Balasubramanian, B., Venkatraman, S., Myint, K. Z., Janvilisri, T., Wongprasert, K., Kumkate, S., Bates, D. O., & Tohtong, R. (2021) · Pharmaceuticals · doi:10.3390/ph14010051 · Cited by 14
Emerging Molecular Dependencies of Mutant EGFR-Driven Non-Small Cell Lung Cancer
Farnsworth, D., Chen, Y. T., de Rappard-Yuswack, G., & Lockwood, W. W. (2021) · Cells · doi:10.3390/cells10123553 · Cited by 16
“Another mechanism of resistance commonly seen in TKI-treated EGFR mutant NSCLC is a shift to a more mesenchymal phenotype that is less dependent on EGFR signaling [76].”
BackgroundEarly T helper cell programming of gene expression in human
Tuomela, S., & Lahesmaa, R. (2013) · Seminars in Immunology · doi:10.1016/j.smim.2013.10.013 · Cited by 14
Challenges and opportunities of translating animal research into human trials in Ethiopia
Abrhaley, A., Giday, M., & Hailu, A. (2024) · BMC Medical Research Methodology · doi:10.1186/s12874-024-02338-8 · Cited by 13
“…attempts to improve translation within the animal research community include the “co-clinical trial” in which preclinical trials explicitly parallel ongoing human phase I and II trials [10] and the development of a scoring system to identify biomarkers that better predict therapeutic success [11].”
BackgroundPrecision preclinical modeling to advance cancer treatment
Gutmann, D. H., Boehm, J. S., Karlsson, E. K., Padron, E., Seshadri, M., WALLIS, D. E., & Snyder, J. C. (2024) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/djae249 · Cited by 14
Modeling K-Ras-driven lung adenocarcinoma in mice: preclinical validation of therapeutic targets
Drosten, M., & Barbacid, M. (2015) · Journal of Molecular Medicine · doi:10.1007/s00109-015-1360-5 · Cited by 12
“Moreover, they induce metastasis more frequently than those GEMMs carrying mutations in the p53 tumor suppressor [38, 39].”
BackgroundZhang, J., Nannapaneni, S., Wang, D., Liu, F., Wang, X., Jin, R., Liu, X., Rahman, M. A., Peng, X., Qian, G., et al. (2017) · Oncotarget · doi:10.18632/oncotarget.19779 · Cited by 13
“However, it is still not clear whether there is a feed-forward loop from LKB1 to ERK, although others [28] and we did observe LKB1 inactivation results in attenuated p-ERK (Figure 1).”
BackgroundSelf-citation
Metadata
- Authors
- Chen, Z., Cheng, K., Walton, Z., Wang, Y., Ebi, H., Shimamura, T., Liu, Y., Tupper, T., Ouyang, J., Li, J., Gao, P., Woo, M. S., Xu, C., Yanagita, M., Altabef, A., Wang, S., Lee, C., Nakada, Y., Peña, C. G., Sun, Y., Franchetti, Y., Yao, C., Saur, A., Cameron, M. D., Nishino, M., Hayes, D. N., Wilkerson, M. D., Roberts, P. J., Lee, C. B., Bardeesy, N., Butaney, M., Chirieac, L. R., Costa, D. B., Jackman, D., Sharpless, N. E., Castrillon, D. H., Demetri, G. D., Jänne, P. A., Pandolfi, P. P., Cantley, L. C., Kung, A. L., Engelman, J. A., & Wong, K.-K.
- Affiliations
- Dana-Farber Cancer Institute (US)
- Brigham and Women's Hospital (US)
- Harvard University (US)
- Loyola University Chicago (US)
- Iowa State University (US)
- University of North Carolina at Chapel Hill (US)
- Harold C. Simmons Comprehensive Cancer Center (US)
- Scripps Research Institute (US)
- Massachusetts General Hospital (US)
- Beth Israel Deaconess Medical Center (US)
- Boston Children's Hospital (US)
- Corresponding author
- Kung, Andrew L.
- Engelman, Jeffrey A.
- Wong, Kwok-Kin
- ORCID
- Cheng, Katherine
- Walton, Zandra
- Wang, Yuchuan
- Ebi, Hiromichi
- Shimamura, Takeshi
- Liu, Yan
- Ouyang, Jing
- Gao, Peng
- Xu, Chunxiao
- Yanagita, Masahiko
- Wang, Shumei
- Lee, Charles
- Nakada, Yuji
- Sun, Yanping
- Franchetti, Yoko
- Cameron, Michael D.
- Nishino, Mizuki
- Hayes, D. Neil
- Wilkerson, Matthew D.
- Roberts, Patrick J.
- Lee, Carrie B.
- Bardeesy, Nabeel
- Butaney, Mohit
- Chirieac, Lucian R.
- Costa, Daniel B.
- Sharpless, Norman E.
- Demetri, George D.
- Pandolfi, Pier Paolo
- Cantley, Lewis C.
- Kung, Andrew L.
- Engelman, Jeffrey A.
- Wong, Kwok-Kin
- Venue
- Nature
- Published
- 2012-03
- Volume
- 483
- Issue
- 7391
- Pages
- 613-617
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3385933
- OpenAlex
- W2094207365
- Cited by
- 446
- References
- 30
- Citations by year
- 2026: 10 · 2025: 7 · 2024: 8 · 2023: 27 · 2022: 13 · 2021: 30 · 2020: 21 · 2019: 29 · 2018: 31 · 2017: 35 · 2016: 42 · 2015: 55 · 2014: 58 · 2013: 62 · 2012: 18
- FWCI
- 49.79
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- American Lung Association
- National Institutes of Health (5k23ca157631-02)
- National Cancer Institute (CA137181, R01CA166480, K23-CA157631, RC2CA147940, R01CA122794, R01CA140594, CA 140594, P50CA090578, CA147940, CA 122794, R01CA137181, CA137008-01, R01CA163896, P01CA120964, R01CA137008, P30CA016086, U01CA141576, CA137008)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Health Sciences › Medicine › Oncology › Lung Cancer Research Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Keywords
- lung cancer, KRAS-mutant lung cancer, co-clinical trials, docetaxel, selumetinib, MEK inhibitors, combination therapy, TP53 mutation, tumor suppressor loss, chemoresistance
- MeSH terms
- Docetaxel, Animals, Antineoplastic Combined Chemotherapy Protocols, Benzimidazoles, Disease Models, Animal, Drug Evaluation, Preclinical, Humans, Lung Neoplasms, Mutation, Pharmacogenetics, Proto-Oncogene Proteins, Tomography, X-Ray Computed, Biomarkers, Tumor, Reproducibility of Results, Randomized Controlled Trials as Topic, Genes, p53, Proto-Oncogene Proteins p21(ras), Treatment Outcome, Clinical Trials, Phase II as Topic, Protein Serine-Threonine Kinases, ras Proteins, Fluorodeoxyglucose F18, Mitogen-Activated Protein Kinase Kinases, MAP Kinase Signaling System, Taxoids, Positron-Emission Tomography, Mice, AMP-Activated Protein Kinases
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