Heightening Energetic Stress Selectively Targets LKB1-Deficient Non–Small Cell Lung Cancers
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Abstract
Inactivation of the LKB1 tumor suppressor is a frequent event in non–small cell lung carcinoma (NSCLC) leading to the activation of mTOR complex 1 (mTORC1) and sensitivity to the metabolic stress inducer phenformin. In this study, we explored the combinatorial use of phenformin with the mTOR catalytic kinase inhibitor MLN0128 as a treatment strategy for NSCLC bearing comutations in the LKB1 and KRAS genes. NSCLC is a genetically and pathologically heterogeneous disease, giving rise to lung tumors of varying histologies that include adenocarcinomas and squamous cell carcinomas (SCC). We demonstrate that phenformin in combination with MLN0128 induced a significant therapeutic response in KRAS/LKB1–mutant human cell lines and genetically engineered mouse models of NSCLC that develop both adenocarcinomas and SCCs. Specifically, we found that KRAS/LKB1–mutant lung adenocarcinomas responded strongly to phenformin + MLN0128 treatment, but the response of SCCs to single or combined treatment with MLN0128 was more attenuated due to acquired resistance to mTOR inhibition through modulation of the AKT-GSK signaling axis. Combinatorial use of the mTOR inhibitor and AKT inhibitor MK2206 robustly inhibited the growth and viability of squamous lung tumors, thus providing an effective strategy to overcome resistance. Taken together, our findings define new personalized therapeutic strategies that may be rapidly translated into clinical use for the treatment of KRAS/LKB1–mutant adenocarcinomas and squamous cell tumors. Cancer Res; 75(22); 4910–22. ©2015 AACR.
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We did not identify targets related to pathways previously investigated for STK11-mutant cancer therapy, such as glutamine synthesis or mTOR signaling.
“we did not identify targets related to pathways previously investigated for STK11-mutant cancer therapy, such as glutamine synthesis (37) or mTOR signaling (38, 39).”
From TNG260 Is a Small-Molecule CoREST Inhibitor That Sensitizes <i>STK11</i> -Mutant Tumors to Anti–PD-1 Immunotherapy (2025) · cites this paper as [38]
LKB1 loss also associates with sensitivity to ER stress caused by 2-deoxy-D-glucose.
“as well as to endoplasmic reticulum stress induced by 2-deoxy-D-glucose158.”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [158]
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Cites
Lynch, T. J., Bell, D. W., Sordella, R., Gurubhagavatula, S., Okimoto, R. A., Brannigan, B. W., Harris, P. L., Haserlat, S. M., Supko, J. G., Haluska, F. G., et al. (2004) · New England Journal of Medicine · doi:10.1056/nejmoa040938 · Cited by 11,486 · see citing works
Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B
Cross, D. A. E., Alessi, D. R., Cohen, P., Andjelkovich, M., & Hemmings, B. A. (1995) · Nature · doi:10.1038/378785a0 · Cited by 5,244 · see citing works
Targeting Hypoxia-Inducible Factors for the Treatment of Anemia in Chronic Kidney Disease Patients
Locatelli, F., Fishbane, S. N., Block, G. A., & Macdougall, I. C. (2017) · American Journal of Nephrology · doi:10.1159/000455166 · Cited by 4,834 · see citing works
Anaplastic Lymphoma Kinase Inhibition in Non–Small-Cell Lung Cancer
Kwak, E. L., Bang, Y., Camidge, D. R., Shaw, A. T., Solomon, B., Maki, R. G., Ou, S. I., Dezube, B. J., Janne, P. A., Costa, D. B., et al. (2010) · New England Journal of Medicine · doi:10.1056/nejmoa1006448 · Cited by 4,442 · see citing works
Comprehensive genomic characterization of squamous cell lung cancers
The Cancer Genome Atlas Research Network (2012) · Nature · doi:10.1038/nature11404 · Cited by 3,994 · see citing works
AMPK Phosphorylation of Raptor Mediates a Metabolic Checkpoint
Gwinn, D. M., Shackelford, D. B., Egan, D. F., Mihaylova, M. M., Mery, A., Vasquez, D. S., Turk, B. E., & Shaw, R. J. (2008) · Molecular Cell · doi:10.1016/j.molcel.2008.03.003 · Cited by 3,849 · see citing works
Self-citationGenotypic and Histological Evolution of Lung Cancers Acquiring Resistance to EGFR Inhibitors
Sequist, L. V., Waltman, B. A., Dias-Santagata, D., Digumarthy, S., Turke, A. B., Fidias, P., Bergethon, K., Shaw, A. T., Gettinger, S., Cosper, A. K., et al. (2011) · Science Translational Medicine · doi:10.1126/scitranslmed.3002003 · Cited by 3,499 · see citing works
Somatic mutations affect key pathways in lung adenocarcinoma
Ding, L., Getz, G., Wheeler, D. A., Mardis, E. R., McLellan, M. D., Cibulskis, K., Sougnez, C., Greulich, H., Muzny, D. M., Morgan, M. B., et al. (2008) · Nature · doi:10.1038/nature07423 · Cited by 2,681 · see citing works
mTOR Inhibition Induces Upstream Receptor Tyrosine Kinase Signaling and Activates Akt
O'Reilly, K. E., Rojo, F., She, Q.-B., Solit, D., Mills, G. B., Smith, D., Lane, H., Hofmann, F., Hicklin, D. J., Ludwig, D. L., et al. (2006) · Cancer Research · doi:10.1158/0008-5472.can-05-2925 · Cited by 2,561 · see citing works
Thoreen, C. C., Kang, S. A., Chang, J. W., Liu, Q., Zhang, J., Gao, Y., Reichling, L. J., Sim, T., Sabatini, D. M., & Gray, N. S. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m900301200 · Cited by 1,803 · see citing works
HIF1α and HIF2α: sibling rivalry in hypoxic tumour growth and progression
Keith, B., Johnson, R. S., & Simon, M. C. (2012) · Nature Reviews Cancer · doi:10.1038/nrc3183 · Cited by 1,693 · see citing works
Manning, B. D., Tee, A. R., Logsdon, M. N., Blenis, J., & Cantley, L. C. (2002) · Molecular Cell · doi:10.1016/s1097-2765(02)00568-3 · Cited by 1,555 · see citing works
A unifying model for mTORC1-mediated regulation of mRNA translation
Thoreen, C. C., Chantranupong, L., Keys, H. R., Wang, T., Gray, N. S., & Sabatini, D. M. (2012) · Nature · doi:10.1038/nature11083 · Cited by 1,477 · see citing works
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 · see citing works
The translational landscape of mTOR signalling steers cancer initiation and metastasis
Hsieh, A. C., Liu, Y., Edlind, M. P., Ingolia, N. T., Janes, M. R., Sher, A., Shi, E. Y., Stumpf, C. R., Christensen, C., Bonham, M. J., et al. (2012) · Nature · doi:10.1038/nature10912 · Cited by 1,313 · see citing works
Active-Site Inhibitors of mTOR Target Rapamycin-Resistant Outputs of mTORC1 and mTORC2
Feldman, M. E., Apsel, B., Uotila, A., Loewith, R., Knight, Z. A., Ruggero, D., & Shokat, K. M. (2009) · PLoS Biology · doi:10.1371/journal.pbio.1000038 · Cited by 1,080 · see citing works
The LKB1 tumor suppressor negatively regulates mTOR signaling
Shaw, R. J., Bardeesy, N. M., Manning, B. D., Lopez, L. V., Kosmatka, M., DePinho, R. A., & Cantley, L. C. (2004) · Cancer Cell · doi:10.1016/j.ccr.2004.06.007 · Cited by 1,067 · see citing works
LKB1 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 · see citing works
Morita, M., Gravel, S.-P., Chénard, V., Sikström, K., Zheng, L., Alain, T., Gandin, V., Avizonis, D., Arguello, M., Zakaria, C., et al. (2013) · Cell Metabolism · doi:10.1016/j.cmet.2013.10.001 · Cited by 842 · see citing works
mTORC1-Mediated Cell Proliferation, But Not Cell Growth, Controlled by the 4E-BPs
Dowling, R. J. O., Topisirović, I., Alain, T., Bidinosti, M., Fonseca, B. D., Petroulakis, E., Wang, X., Larsson, O. S., Selvaraj, A., Liu, Y., et al. (2010) · Science · doi:10.1126/science.1187532 · Cited by 726 · see citing works
Effects of metformin and other biguanides on oxidative phosphorylation in mitochondria
Bridges, H. R., Jones, A. J. Y., Pollak, M. N., & Hirst, J. (2014) · Biochemical Journal · doi:10.1042/bj20140620 · Cited by 661 · see citing works
Inactivation of LKB1/STK11 is a common event in adenocarcinomas of the lung.
Sánchez‐Céspedes, M., Parrella, P., Esteller, M., Nomoto, S., Trink, B., Engles, J. M., Westra, W. H., Herman, J. G., & Sidransky, D. (2002) · PubMed · Cited by 626 · see citing works
Shackelford, D. B., Abt, E., Gerken, L., Vasquez, D. S., Seki, A., Leblanc, M., Wei, L., Fishbein, M. C., Czernin, J., Mischel, P. S., et al. (2013) · Cancer Cell · doi:10.1016/j.ccr.2012.12.008 · Cited by 585 · see citing works
Self-citationWei, G., Twomey, D., Lamb, J., Schlis, K. D., Agarwal, J., Stam, R. W., Opferman, J. T., Sallan, S. E., den Boer, M. L., Pieters, R., et al. (2006) · Cancer Cell · doi:10.1016/j.ccr.2006.09.006 · Cited by 505 · see citing works
A murine lung cancer co-clinical trial identifies genetic modifiers of therapeutic response
Chen, Z., Cheng, K., Walton, Z., Wang, Y., Ebi, H., Shimamura, T., Liu, Y., Tupper, T., Ouyang, J., Li, J., et al. (2012) · Nature · doi:10.1038/nature10937 · Cited by 446 · cited 2× · see citing works
“P-Erk staining was not detectable in KLluc lung tumors (data not shown), which agrees with previously published reports (29).”
mTOR Kinase Inhibition Causes Feedback-Dependent Biphasic Regulation of AKT Signaling
Rodrik-Outmezguine, V. S., Chandarlapaty, S., Pagano, N. C., Poulikakos, P. I., Scaltriti, M., Moskatel, E., Baselga, J., Guichard, S., & Rosen, N. (2011) · Cancer Discovery · doi:10.1158/2159-8290.cd-11-0085 · Cited by 442 · see citing works
Wander, S. A., Hennessy, B. T., & Slingerland, J. M. (2011) · Journal of Clinical Investigation · doi:10.1172/jci44145 · Cited by 427 · see citing works
She, Q.-B., Halilovic, E., Ye, Q., Zhen, W., Shirasawa, S., Sasazuki, T., Solit, D. B., & Rosen, N. (2010) · Cancer Cell · doi:10.1016/j.ccr.2010.05.023 · Cited by 400 · cited 1× · see citing works
“We took advantage of a doxycycline (dox)-inducible mutant 4E-BP1 4Ala (4E-BP1 4A) that constitutively binds eIF4E to inhibit cap-dependent translation (22, 23).”
Loss of Lkb1 and Pten Leads to Lung Squamous Cell Carcinoma with Elevated PD-L1 Expression
Xu, C., Brainson, C. F., Koyama, S., Wu, H., Zhao, Y., Chen, Z., Herter-Sprie, G. S., Akbay, E. A., Tchaicha, J. H., Altabef, A. B., et al. (2014) · Cancer Cell · doi:10.1016/j.ccr.2014.03.033 · Cited by 394 · see citing works
Squamous Cell Carcinoma of the Lung: Molecular Subtypes and Therapeutic Opportunities
Perez-Moreno, P., Brambilla, E. M., Thomas, R. K., & Soria, J. (2012) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-11-2370 · Cited by 347 · see citing works
Elkabets, M., Vora, S., Juric, D., Morse, N., Mino-Kenudson, M., Muranen, T., Tao, J., Campos, A. B., Rodon, J., Ibrahim, Y. H., et al. (2013) · Science Translational Medicine · doi:10.1126/scitranslmed.3005747 · Cited by 332 · see citing works
Rozengurt, E., Soares, H. P., & Sinnet-Smith, J. (2014) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-14-0330 · Cited by 316 · see citing works
Wilkerson, M. D., Yin, X., Walter, V., Zhao, N., Cabanski, C. R., Hayward, M. C., Miller, C. R., Socinski, M. A., Parsons, A. M., Thorne, L. B., et al. (2012) · PLoS ONE · doi:10.1371/journal.pone.0036530 · Cited by 300 · see citing works
Pourdehnad, M., Truitt, M., Siddiqi, I. N., Ducker, G. S., Shokat, K. M., & Ruggero, D. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1310230110 · Cited by 288 · see citing works
Loss of the Tumor Suppressor LKB1 Promotes Metabolic Reprogramming of Cancer Cells via HIF-1α
Faubert, B., Vincent, E. E., Griss, T., Samborska, B., Izreig, S., Svensson, R. U., Mamer, O. A., Avizonis, D., Shackelford, D. B., Shaw, R. J., et al. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1312570111 · Cited by 278 · see citing works
Self-citationDykens, J. A., Jamieson, J., Marroquin, L., Nadanaciva, S., Billis, P. A., & Will, Y. (2008) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2008.08.013 · Cited by 220 · cited 1× · see citing works
“Furthermore, phenformin actively induces a cellular switch to glycolytic metabolism (41, 42), which explains the expansion of FDG avid phenformin-resistant SCCs we observe in KLluc mice (Figs.”
mTOR and HIF-1α-mediated tumor metabolism in an LKB1 mouse model of Peutz-Jeghers syndrome
Shackelford, D. B., Vasquez, D. S., Corbeil, J., Wu, S., Leblanc, M., Wu, C., Vera, D. R., & Shaw, R. J. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0900465106 · Cited by 204 · see citing works
Self-citationSu, H. C., Bodenstein, C., Dumont, R. A., Seimbille, Y., Dubinett, S. M., Phelps, M. E., Herschman, H. R., Czernin, J. G., & Weber, W. (2006) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-06-0368 · Cited by 202 · see citing works
Self-citationTransdifferentiation of lung adenocarcinoma in mice with Lkb1 deficiency to squamous cell carcinoma
Han, X., Li, F., Fang, Z., Gao, Y., Li, F., Fang, R., Yao, S., Sun, Y., Li, L., Zhang, W., et al. (2014) · Nature Communications · doi:10.1038/ncomms4261 · Cited by 193 · see citing works
Li, F., Han, X., Li, F., Wang, R., Wang, H., Gao, Y., Wang, X., Fang, Z., Zhang, W., Yao, S., et al. (2015) · Cancer Cell · doi:10.1016/j.ccell.2015.04.001 · Cited by 169 · see citing works
Differential effects of AMPK agonists on cell growth and metabolism
Vincent, E. E., Coelho, P. P., Blagih, J., Griss, T., Viollet, B., & Jones, R. G. (2014) · Oncogene · doi:10.1038/onc.2014.301 · Cited by 155 · see citing works
Faber, A. C., Coffee, E. M., Costa, C., Dastur, A., Ebi, H., Hata, A. N., Yeo, A. T., Edelman, E. J., Song, Y., Tam, A. T., et al. (2014) · Cancer Discovery · doi:10.1158/2159-8290.cd-13-0315 · Cited by 124 · see citing works
Palaskas, N. J., Larson, S. M., Schultz, N. D., Komisopoulou, E., Wong, J., Rohle, D., Campos, C., Yannuzzi, N. A., Osborne, J. R., Linkov, I., et al. (2011) · Cancer Research · doi:10.1158/0008-5472.can-10-4633 · Cited by 123 · see citing works
Sox2 Cooperates with Lkb1 Loss in a Mouse Model of Squamous Cell Lung Cancer
Mukhopadhyay, A., Berrett, K. C., Kc, U., Clair, P. M., Pop, S., Carr, S. R., Witt, B. L., & Oliver, T. G. (2014) · Cell Reports · doi:10.1016/j.celrep.2014.05.036 · Cited by 103 · see citing works
Slotkin, E. K., Patwardhan, P. P., Vasudeva, S. D., de Stanchina, E., Tap, W. D., & Schwartz, G. K. (2014) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-14-0711 · Cited by 98 · see citing works
Defining Key Signaling Nodes and Therapeutic Biomarkers in NF1 -Mutant Cancers
Malone, C. F., Longo, J. F., Maertens, O., Raedt, T. D., Ingraham, R., & Cichowski, K. M. (2014) · Cancer Discovery · doi:10.1158/2159-8290.cd-14-0159 · Cited by 65 · see citing works
Preuß, E., Hugle, M., Reimann, R., Schlecht, M., & Fulda, S. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.495986 · Cited by 62 · see citing works
Liang, M.-C., Ma, J., Chen, L., Kozłowski, P., Qin, W., Li, D. D., Goto, J., Shimamura, T., Hayes, D. N., Meyerson, M. M., et al. (2009) · Oncogene · doi:10.1038/onc.2009.452 · Cited by 54 · see citing works
mTOR ATP-competitive inhibitor INK128 inhibits neuroblastoma growth via blocking mTORC signaling
Zhang, H., Dou, J., Yu, Y., Zhao, Y., Fan, Y., Cheng, J., Xu, X. Y., Liu, W. Y., Guan, S., Chen, Z., et al. (2014) · APOPTOSIS · doi:10.1007/s10495-014-1066-0 · Cited by 49 · see citing works
Lou, H., Weng, X.-C., Pan, H., Qin, P., Sun, P., Liu, L.-L., & Chen, B. (2014) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2014.06.081 · Cited by 27 · see citing works
Andrade-Vieira, R., Goguen, D., Bentley, H. A., Bowen, C. V., & Marignani, P. A. (2014) · Oncotarget · doi:10.18632/oncotarget.2818 · Cited by 24 · see citing works
Borland, R., & Webber, A. J. (1966) · PubMed · Cited by 14 · see citing works
Fukunaga, T., Enomoto, K., Okazumi, S., Kikuchi, T., Yamamoto, H., Koide, Y., & Isono, K. (1994) · PubMed · Cited by 12 · see citing works
Flagged first, then by citations
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Research works printed but not linked: 1
- [20]Thoreen CC Kang SA Chang JW Liu Q Zhang J Gao Y An ATP-competitive mTOR inhibitor reveals rapamycin-insensitive functions of mTORC1. J Biol Chem 2009 PMC2658096 19150980
Cited by
Sorted by citations
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 · see citing works
Galan-Cobo, A., Sitthideatphaiboon, P., Qu, X., Poteete, A., Pisegna, M. A., Tong, P., Chen, P.-H., Boroughs, L. K., Rodriguez, M. L. M., Zhang, W., et al. (2019) · Cancer Research · doi:10.1158/0008-5472.can-18-3527 · Cited by 292 · see citing works
In vivo imaging of mitochondrial membrane potential in non-small-cell lung cancer
Momcilovic, M., Jones, A., Bailey, S. T., Waldmann, C. M., Li, R., Lee, J. T., Abdelhady, G., Gomez, A., Holloway, T., Schmid, E., et al. (2019) · Nature · doi:10.1038/s41586-019-1715-0 · Cited by 214 · see citing works
Self-citationLi, H., Li, X., Liu, S., Guo, L., Zhang, B., Zhang, J., & Ye, Q. (2017) · Hepatology · doi:10.1002/hep.29360 · Cited by 193 · see citing works
The GSK3 Signaling Axis Regulates Adaptive Glutamine Metabolism in Lung Squamous Cell Carcinoma
Momcilovic, M., Bailey, S. T., Lee, J. T., Fishbein, M. C., Braas, D., Go, J. L., Graeber, T. G., Parlati, F., Demo, S. D., Li, R., et al. (2018) · Cancer Cell · doi:10.1016/j.ccell.2018.04.002 · Cited by 182 · see citing works
Self-citationTargeted inhibition of EGFR and glutaminase induces metabolic crisis in EGFR mutant lung cancer
Momcilovic, M., Bailey, S. T., Lee, J. T., Fishbein, M. C., Magyar, C., Braas, D., Graeber, T., Jackson, N. J., Czernin, J., Emberley, E., et al. (2017) · Cell Reports · doi:10.1016/j.celrep.2016.12.061 · Cited by 157 · see citing works
Self-citationSpatial mapping of mitochondrial networks and bioenergetics in lung cancer
Han, M., Bushong, E. A., Segawa, M., Tiard, A., Wong, A., Brady, M. R., Momcilovic, M., Wolf, D. M., Zhang, R., Petcherski, A., et al. (2023) · Nature · doi:10.1038/s41586-023-05793-3 · Cited by 168 · see citing works
Self-citationGoodwin, J., Neugent, M. L., Lee, S. Y., Choe, J. H., Choi, H., Jenkins, D. M. R., Ruthenborg, R. J., Robinson, M. W., Jeong, J. Y., Wake, M., et al. (2017) · Nature Communications · doi:10.1038/ncomms15503 · Cited by 151 · see citing works
Self-citationLKB1 deficiency-induced metabolic reprogramming in tumorigenesis and non-neoplastic diseases
Zhang, Y., Meng, Q., Sun, Q., Xu, Z., Zhou, H., & Wang, Y. (2020) · Molecular Metabolism · doi:10.1016/j.molmet.2020.101131 · Cited by 90 · see citing works
Crosstalks of GSK3 signaling with the mTOR network and effects on targeted therapy of cancer
Evangelisti, C., Chiarini, F., Paganelli, F., Marmiroli, S., & Martelli, A. M. (2019) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2019.118635 · Cited by 80 · see citing works
Therapeutic Repurposing of Biguanides in Cancer
Zhao, H., Swanson, K. D., & Zheng, B. (2021) · Trends in cancer · doi:10.1016/j.trecan.2021.03.001 · Cited by 65 · see citing works
LKB1 promotes metabolic flexibility in response to energy stress
Parker, S. J., Svensson, R. U., Divakaruni, A. S., Lefebvre, A. E. Y. T., Murphy, A. N., Shaw, R. J., & Metallo, C. M. (2016) · Metabolic Engineering · doi:10.1016/j.ymben.2016.12.010 · Cited by 52 · see citing works
Targeting Myc-driven stress addiction in colorectal cancer
Saeed, H., Leibowitz, B. J., Zhang, L., & Yu, J. (2023) · Drug Resistance Updates · doi:10.1016/j.drup.2023.100963 · Cited by 53 · see citing works
Metformin for non-small cell lung cancer patients: Opportunities and pitfalls
Lévy, A., & Doyen, J. (2018) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2018.03.001 · Cited by 46 · see citing works
de Mey, S., Jiang, H., Corbet, C., Wang, H., Dufait, I., Ka, L. L., Bastien, E., Verovski, V. N., Gevaert, T., Féron, O., et al. (2018) · Frontiers in Pharmacology · doi:10.3389/fphar.2018.01073 · Cited by 45 · see citing works
Momcilovic, M., & Shackelford, D. B. (2017) · Biomolecules & Therapeutics · doi:10.4062/biomolther.2017.220 · Cited by 42 · see citing works
Self-citationMetabolic Rewiring in Response to Biguanides Is Mediated by mROS/HIF-1a in Malignant Lymphocytes
Khan, H., Anshu, A., Prasad, A. K., Roy, S., Jeffery, J. J., Kittipongdaja, W., Yang, D. T., & Schieke, S. M. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.11.007 · Cited by 41 · see citing works
The Liver Circadian Clock Modulates Biochemical and Physiological Responses to Metformin
Henriksson, E., Huber, A., Soto, E., Kriebs, A., Vaughan, M. E., Duglan, D., Chan, A. B., Papp, S. J., Nguyen, M., Afetian, M. E., et al. (2017) · Journal of Biological Rhythms · doi:10.1177/0748730417710348 · Cited by 36 · see citing works
Zou, A., Wu, A., Luo, M., Zhou, C., Lu, Y., & Yu, X. (2019) · Life Sciences · doi:10.1016/j.lfs.2019.116798 · Cited by 34 · see citing works
Repression of LKB1 by miR-17∼92 Sensitizes MYC-Dependent Lymphoma to Biguanide Treatment
Izreig, S., Gariepy, A., Kaymak, I., Bridges, H. R., Donayo, A. O., Bridon, G., DeCamp, L. M., Kitchen-Goosen, S. M., Avizonis, D. Z., Sheldon, R. D., et al. (2020) · Cell Reports Medicine · doi:10.1016/j.xcrm.2020.100014 · Cited by 32 · see citing works
Kaufman, 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 · see citing works
Antonia, R. J., & Baldwin, A. S. (2018) · Science Signaling · doi:10.1126/scisignal.aan5850 · Cited by 30 · see citing works
Chiarini, F., Evangelisti, C., Lattanzi, G., McCubrey, J. A., & Martelli, A. M. (2019) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2019.03.013 · Cited by 31 · see citing works
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Ndembe, G., Intini, I., Perin, E., Marabese, M., Caiola, E., Mendogni, P., Rosso, L., Broggini, M., & Colombo, M. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.889826 · Cited by 24 · see citing works
Shining a light on metabolic vulnerabilities in non-small cell lung cancer
Dowling, C. M., Zhang, H., Chonghaile, T. N., & Wong, K.-K. (2021) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2020.188462 · Cited by 26 · see citing works
“reduction in metabolic plasticity when dealing with energy crisis [70, 73].”
BackgroundNärhi, 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 25 · see citing works
Li, X., Li, B., Ni, Z., Zhou, P., Wang, B., He, J., Xiong, H., Yang, F., Wu, Y., Lyu, X., et al. (2017) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-16-0763 · Cited by 23 · see citing works
Hsieh, F., Hung, M., Wang, C.-Y., Chen, Y., Hsiao, Y., Tsai, M.-H., Li, J., Chen, L., Shih, C.-T., Chao, T., et al. (2017) · Lung Cancer · doi:10.1016/j.lungcan.2017.07.040 · Cited by 24 · see citing works
Guo, W., Kuang, Y., Wu, J., Donghua, W., Zhou, A., Liao, Y., Song, H., Xu, D., Wang, T., Jing, B., et al. (2020) · Frontiers in Oncology · doi:10.3389/fonc.2020.00052 · Cited by 20 · see citing works
Targeting Therapy Resistance: When Glutamine Catabolism Becomes Essential
Lukey, M. J., Katt, W. P., & Cerione, R. A. (2018) · Cancer Cell · doi:10.1016/j.ccell.2018.04.009 · Cited by 19 · see citing works
Research progress on the therapeutic effect and mechanism of metformin for lung cancer (Review)
Han, P., Zhou, J., Xiang, J., Liu, Q., & Sun, K. (2022) · Oncology Reports · doi:10.3892/or.2022.8440 · Cited by 15 · see citing works
Metabolic Phenotypes, Dependencies, and Adaptation in Lung CancerPreprint
DeNicola, G. M., & Shackelford, D. B. (2021) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a037838 · Cited by 13 · see citing works
Self-citationMomcilovic, M., Bailey, S. T., Lee, J. T., Zamilpa, C., Jones, A. E., Abdelhady, G., Mansfield, J. R., Francis, K. P., & Shackelford, D. B. (2018) · Journal of Visualized Experiments · doi:10.3791/57167 · Cited by 13 · see citing works
Self-citationGeroyska, S., Mejia, I., Chan, A. A., Navarrete, M. S., Pandey, V., Kharpatin, S., Noguti, J., Wang, F., Srole, D. N., Chou, T., et al. (2024) · Cancer Research Communications · doi:10.1158/2767-9764.crc-23-0428 · Cited by 10 · see citing works
Self-citationAhronian, L. G., Sahu, S., Zhang, M., Patel, A. S., Geng, K., Bhattacharya, R., Falchook, G. S., Goldman, J. W., Spira, A. I., Punekar, S. R., et al. (2025) · Cancer Research · doi:10.1158/0008-5472.can-25-0998 · Cited by 9 · see citing works
“Accordingly, we did not identify targets related to pathways previously investigated for STK11 -mutant cancer therapy, such as glutamine synthesis (37) or mTOR signaling (38, 39).”
Regulating T Cell Population Alleviates SLE by Inhibiting mTORC1/C2 in MRL/lpr Mice
Zhang, D., Wang, M., Shi, G., Pan, P., Ji, J., & Li, P. (2021) · Frontiers in Pharmacology · doi:10.3389/fphar.2020.579298 · Cited by 10 · see citing works
Imaging the Rewired Metabolism in Lung Cancer in Relation to Immune Therapy
van Genugten, E. A. J., Weijers, J. A., Heskamp, S., Kneilling, M., van den Heuvel, M., Piet, B., Bussink, J., Hendriks, L., & Aarntzen, E. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2021.786089 · Cited by 8 · see citing works
Huang, J., Chen, H.-W., Wei, Q., Zhang, Z., Zhong, Z., & Xu, Y. (2017) · Oncology Letters · doi:10.3892/ol.2017.5631 · Cited by 8 · see citing works
A phase II trial of mTORC1/2 inhibition in STK11 deficient non small cell lung cancer
Middleton, G., Robbins, H. L., Fletcher, P., Savage, J., Mehmi, M., Summers, Y., Greystoke, A., Steele, N., Popat, S., Jain, P., et al. (2025) · npj Precision Oncology · doi:10.1038/s41698-025-00838-4 · Cited by 7 · see citing works
Novel putative drivers revealed by targeted exome sequencing of advanced solid tumors
Pannuti, A., Filipović, A., Hicks, C., Lefkowitz, E. J., Ptacek, T., Stebbing, J., & Miele, L. (2018) · PLoS ONE · doi:10.1371/journal.pone.0194790 · Cited by 7 · see citing works
Progress in antitumor mechanisms and applications of phenformin (Review)
Zhong, Q., Li, D., & Yang, X. (2024) · Oncology Reports · doi:10.3892/or.2024.8810 · Cited by 6 · see citing works
Momcilovic, M., Bailey, S. T., Lee, J. T., Zamilpa, C., Jones, A., Abdelhady, G. A., Mansfield, J. R., Francis, K. P., & Shackelford, D. B. (2018) · Journal of Visualized Experiments · doi:10.3791/57167-v · Cited by 1 · see citing works
Self-citationNagaraj, A. S. (2018) · Työväentutkimus Vuosikirja
Chandel, N. S. (2019) · Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature · doi:10.3410/f.736825985.793567150
A proteomic approach for understanding the metabolic adaptations in non-small cell lung cancer
Martín-Bernabé, A. (2018) · theses.fr (ABES) · doi:10.70675/426e7b40z057az4326z8cfez7da3a5c12c7e
STK11/LKB1 Loss in Cancer: From Developmental Constraint to Stress-Adapted Malignancy
Kang, Y., Gao, Y., Zhang, X., Liu, H.-O., Xu, C., & Huo, Y. (2026) · Cancers · doi:10.3390/cancers18172845
- Authors
- Momcilovic, M., McMickle, R., Abt, E., Seki, A., Simko, S. A., Magyar, C., Stout, D. B., Fishbein, M. C., Walser, T. C., Dubinett, S. M., & Shackelford, D. B.
- Affiliations
- University of California, Los Angeles (US)
- Corresponding author
- Shackelford, David B.
- ORCID
- Venue
- Cancer Research
- Published
- 2015-11-15
- Volume
- 75
- Issue
- 22
- Pages
- 4910-4922
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- PMC
- PMC4654699
- OpenAlex
- W2179686101
- Cited by
- 46
- References
- 55
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 2 · 2023: 2 · 2022: 3 · 2021: 3 · 2020: 4 · 2019: 8 · 2018: 11 · 2017: 8 · 2016: 2
- FWCI
- 3.04
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institutes of Health (UL1TR000124, KL2TR000122)
- National Cancer Institute (P30CA016042)
- National Center for Advancing Translational Sciences
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- LKB1, non-small cell lung cancer, phenformin, MLN0128, mTOR inhibition, KRAS mutation, metabolic stress, acquired drug resistance, lung adenocarcinoma, squamous cell carcinoma, MK-2206, combination therapy, precision oncology
- MeSH terms
- AMP-Activated Protein Kinase Kinases, Adenine, Animals, Antineoplastic Combined Chemotherapy Protocols, Benzoxazoles, Carcinoma, Non-Small-Cell Lung, Disease Models, Animal, Humans, Immunohistochemistry, Lung Neoplasms, Phenformin, Pyrimidines, Stress, Physiological, Proto-Oncogene Proteins p21(ras), Apoptosis, Protein Serine-Threonine Kinases, Cell Line, Tumor, Mice, AMP-Activated Protein Kinases
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