Combination of ERK and autophagy inhibition as a treatment approach for pancreatic cancer
Open accessAbstract
Pancreatic ductal adenocarcinoma (PDAC) is characterized by KRAS- and autophagy-dependent tumorigenic growth, but the role of KRAS in supporting autophagy has not been established. We show that, to our surprise, suppression of KRAS increased autophagic flux, as did pharmacological inhibition of its effector ERK MAPK. Furthermore, we demonstrate that either KRAS suppression or ERK inhibition decreased both glycolytic and mitochondrial functions. We speculated that ERK inhibition might thus enhance PDAC dependence on autophagy, in part by impairing other KRAS- or ERK-driven metabolic processes. Accordingly, we found that the autophagy inhibitor chloroquine and genetic or pharmacologic inhibition of specific autophagy regulators synergistically enhanced the ability of ERK inhibitors to mediate antitumor activity in KRAS-driven PDAC. We conclude that combinations of pharmacologic inhibitors that concurrently block both ERK MAPK and autophagic processes that are upregulated in response to ERK inhibition may be effective treatments for PDAC.
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In KRAS-mutant pancreatic cancer cells, blocking the MAPK pathway reduces glucose uptake.
“In KRAS mutant pancreatic cancer cells, inhibition of the MAPK pathway downregulates glucose uptake and forces the cell to become more dependent on autophagy for survival (95, 96).”
From KRAS mutation in pancreatic cancer (2021) · cites this paper as [96]
In KRAS-mutant pancreatic cancer cells, MAPK pathway inhibition makes the cells more reliant on autophagy to survive.
“In KRAS mutant pancreatic cancer cells, inhibition of the MAPK pathway downregulates glucose uptake and forces the cell to become more dependent on autophagy for survival (95, 96).”
From KRAS mutation in pancreatic cancer (2021) · cites this paper as [96]
In KRAS-mutant pancreatic cancer cells, the autophagy pathway acts as a collateral dependency alongside MAPK pathway inhibition.
“Recently, through combinatorial RNAi screens and hypothesis-driven approaches, we and others have identified the autophagy pathway as a collateral dependency partner with MAPK pathway inhibitors in pancreatic cancer cells with KRAS mutation (30, 95, 96).”
From KRAS mutation in pancreatic cancer (2021) · cites this paper as [96]
Blocking autophagy by concomitant inhibition of autophagy and MEK or ERK kinases is likely to be therapeutically beneficial in patients with KRAS-mutant pancreatic ductal adenocarcinoma, NRAS-mutant melanoma, and BRAF-mutant colorectal cancer.
“blocking this protective mechanism by concomitant inhibition of autophagy and MEK or ERK kinases is likely to be therapeutically beneficial in patients with KRAS-mutant pancreatic ductal adenocarcinoma, NRAS-mutant melanoma, and BRAF-mutant colorectal cancer (66, 67).”
From New Horizons in KRAS-Mutant Lung Cancer: Dawn After Darkness (2019) · cites this paper as [66]
Three simultaneously published studies indicated that upon inhibition of the MAPK pathway, KRAS-mutant tumors depend on autophagy for survival.
“These studies indicated that upon the inhibition of the MAPK pathway, KRAS-mutant tumors depend on autophagy for survival”
From New Horizons in KRAS-Mutant Lung Cancer: Dawn After Darkness (2019) · cites this paper as [66]
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Repertoires of Autophagy in the Pathogenesis of Ocular Diseases
Li, Y., Jiang, Q. L., Cao, G.-F., Yao, J., & Yan, B. (2015) · Cellular Physiology and Biochemistry · doi:10.1159/000373980 · Cited by 16,351 · see citing works
GSVA: gene set variation analysis for microarray and RNA-Seq data
Hänzelmann, S., Castelo, R., & Guinney, J. (2013) · BMC Bioinformatics · doi:10.1186/1471-2105-14-7 · Cited by 15,440 · see citing works
AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1
Kim, J., Kundu, M., Viollet, B., & Guan, K.-L. (2011) · Nature Cell Biology · doi:10.1038/ncb2152 · Cited by 7,227 · see citing works
Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition).
Klionsky, D. J., Abdelmohsen, K., Abe, A., Abedin, M. J., Abeliovich, H., Acevedo Arozena, A., Adachi, H., Adams, C. M., Adams, P. D., Adeli, K., et al. (2016) · Autophagy · doi:10.1080/15548627.2015.1100356 · Cited by 5,894 · see citing works
Self-citationPreinvasive and invasive ductal pancreatic cancer and its early detection in the mouse
Hingorani, S. R., Petricoin, E. F., Maitra, A., Rajapakse, V., King, C., Jacobetz, M. A., Ross, S., Conrads, T. P., Veenstra, T. D., Hitt, B. A., et al. (2003) · Cancer Cell · doi:10.1016/s1535-6108(03)00309-x · Cited by 2,471 · see citing works
Self-citationRyan, D. P., Hong, T. S., & Bardeesy, N. (2014) · New England Journal of Medicine · doi:10.1056/nejmra1404198 · Cited by 2,348 · see citing works
Oncogenic Kras maintains pancreatic tumors through regulation of anabolic glucose metabolism
Ying, H., Kimmelman, A. C., Lyssiotis, C. A., Hua, S., Chu, G. C., Fletcher-Sananikone, E., Locasale, J. W., Son, J., Zhang, H., Coloff, J. L., et al. (2012) · Cell · doi:10.1016/j.cell.2012.01.058 · Cited by 2,043 · see citing works
Self-citationDrugging 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 · see citing works
Self-citationRabinowitz, J. D., & White, E. (2010) · Science · doi:10.1126/science.1193497 · Cited by 1,982 · see citing works
Macropinocytosis of protein is an amino acid supply route in Ras-transformed cells
Commisso, C., Davidson, S. M., Soydaner-Azeloglu, R. G., Parker, S. J., Kamphorst, J. J., Hackett, S., Grabocka, E., Nofal, M., Drebin, J. A., Thompson, C. B., et al. (2013) · Nature · doi:10.1038/nature12138 · Cited by 1,683 · see citing works
Pancreatic cancers require autophagy for tumor growth
Yang, S., Wang, X., Contino, G., Liesa, M., Sahin, E., Ying, H., Bause, A., Li, Y., Stommel, J. M., Dell'Antonio, G., et al. (2011) · Genes & Development · doi:10.1101/gad.2016111 · Cited by 1,498 · see citing works
Self-citationLC3, GABARAP and GATE16 localize to autophagosomal membrane depending on form-II formation
Kabeya, Y., Mizushima, N., Yamamoto, A., Oshitani-Okamoto, S., Ohsumi, Y., & Yoshimori, T. (2004) · Journal of Cell Science · doi:10.1242/jcs.01131 · Cited by 1,394 · see citing works
Activated Ras requires autophagy to maintain oxidative metabolism and tumorigenesis
Guo, J. Y., Chen, H.-Y., Mathew, R., Fan, J., Strohecker, A. M., Karsli-Uzunbas, G., Kamphorst, J. J., Chen, G., Lemons, J. M. S., Karantza, V., et al. (2011) · Genes & Development · doi:10.1101/gad.2016311 · Cited by 1,323 · see citing works
Oncogene ablation-resistant pancreatic cancer cells depend on mitochondrial function
Viale, A., Pettazzoni, P., Lyssiotis, C. A., Ying, H., Sánchez, N., Marchesini, M., Carugo, A., Green, T., Seth, S., Giuliani, V., et al. (2014) · Nature · doi:10.1038/nature13611 · Cited by 1,259 · see citing works
Self-citationTargeting KRAS mutant cancers with a covalent G12C-specific inhibitor
Janes, M. R., Zhang, J., Li, L.-S., Hansen, R., Peters, U., Guo, X., Chen, Y., Babbar, A., Firdaus, S. J., Darjania, L., et al. (2018) · Cell · doi:10.1016/j.cell.2018.01.006 · Cited by 1,172 · see citing works
Self-citationOrganoid Profiling Identifies Common Responders to Chemotherapy in Pancreatic Cancer
Tiriac, H., Belleau, P., Engle, D. D., Plenker, D., Deschênes, A., Somerville, T. D. D., Froeling, F. E. M., Burkhart, R. A., Denroche, R. E., Jang, G.-H., et al. (2018) · Cancer Discovery · doi:10.1158/2159-8290.cd-18-0349 · Cited by 1,092 · see citing works
KRAS: The Critical Driver and Therapeutic Target for Pancreatic Cancer
Waters, A. M., & Der, C. J. (2018) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a031435 · Cited by 875 · see citing works
Self-citationBeclin1 Controls the Levels of p53 by Regulating the Deubiquitination Activity of USP10 and USP13
Liu, J., Xia, H., Kim, M., Xu, L., Li, Y., Zhang, L., Cai, Y. C., Norberg, H. V., Zhang, T., Furuya, T., et al. (2011) · Cell · doi:10.1016/j.cell.2011.08.037 · Cited by 828 · see citing works
Mitochondrial Cristae: Where Beauty Meets Functionality
Cogliati, S., Enriquez, J. A., & Scorrano, L. (2016) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2016.01.001 · Cited by 816 · see citing works
Stephen, A. G., Esposito, D., Bagni, R. K., & McCormick, F. (2014) · Cancer Cell · doi:10.1016/j.ccr.2014.02.017 · Cited by 795 · see citing works
Oncogenic Kras is required for both the initiation and maintenance of pancreatic cancer in mice
Collins, M. A., Bednar, F., Zhang, Y., Brisset, J.-C., Galbán, S., Galbán, C. J., Rakshit, S., Flannagan, K. S., Adsay, N. V., & Pasca di Magliano, M. (2012) · Journal of Clinical Investigation · doi:10.1172/jci59227 · Cited by 770 · see citing works
Small Molecule Inhibition of the Autophagy Kinase ULK1 and Identification of ULK1 Substrates
Egan, D. F., Chun, M. G. H., Vamos, M., Zou, H., Rong, J., Miller, C. J., Lou, H. J., Raveendra-Panickar, D., Yang, C.-C., Sheffler, D. J., et al. (2015) · Molecular Cell · doi:10.1016/j.molcel.2015.05.031 · Cited by 715 · see citing works
Erk2 Phosphorylation of Drp1 Promotes Mitochondrial Fission and MAPK-Driven Tumor Growth
Kashatus, J. A., Nascimento, A., Myers, L. J., Sher, A., Byrne, F. L., Hoehn, K. L., Counter, C. M., & Kashatus, D. F. (2015) · Molecular Cell · doi:10.1016/j.molcel.2015.01.002 · Cited by 700 · see citing works
Morris, E. J., Jha, S., Restaino, C. R., Dayananth, P., Zhu, H., Cooper, A., Carr, D., Deng, Y., Jin, W., Black, S., et al. (2013) · Cancer Discovery · doi:10.1158/2159-8290.cd-13-0070 · Cited by 676 · see citing works
KRAS: feeding pancreatic cancer proliferation
Bryant, K. L., Mancias, J. D., Kimmelman, A. C., & Der, C. J. (2014) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2013.12.004 · Cited by 675 · see citing works
Self-citationKinsey, C. G., Camolotto, S. A., Boespflug, A. M., Guillen, K. P., Foth, M., Truong, A., Schuman, S. S., Shea, J. E., Seipp, M. T., Yap, J. T., et al. (2019) · Nature Medicine · doi:10.1038/s41591-019-0367-9 · Cited by 634 · see citing works
Shukla, S. K., Purohit, V., Mehla, K., Gunda, V., Chaika, N. V., Vernucci, E., King, R. J., Abrego, J., Goode, G. D., Dasgupta, A., et al. (2017) · Cancer Cell · doi:10.1016/j.ccell.2017.06.004 · Cited by 542 · see citing works
Self-citationAutophagy is critical for pancreatic tumor growth and progression in tumors with p53 alterations
Yang, A., Rajeshkumar, N. V., Wang, X., Yabuuchi, S., Alexander, B. M., Chu, G. C., Von Hoff, D. D., Maitra, A., & Kimmelman, A. C. (2014) · Cancer Discovery · doi:10.1158/2159-8290.cd-14-0362 · Cited by 486 · see citing works
Self-citationTargeting ER stress–induced autophagy overcomes BRAF inhibitor resistance in melanoma
Ma, X.-H., Piao, S.-F., Dey, S., Mcafee, Q., Karakousis, G., Villanueva, J., Hart, L. S., Levi, S., Hu, J., Zhang, G., et al. (2014) · Journal of Clinical Investigation · doi:10.1172/jci70454 · Cited by 457 · see citing works
Self-citationSullivan, R. J., Infante, J. R., Jankú, F., Wong, D. J. L., Sosman, J. A., Keedy, V. L., Patel, M. R., Shapiro, G. I., Mier, J. W., Tolcher, A. W., et al. (2017) · Cancer Discovery · doi:10.1158/2159-8290.cd-17-1119 · Cited by 436 · see citing works
Papke, B., & Der, C. J. (2017) · Science · doi:10.1126/science.aam7622 · Cited by 399 · see citing works
Self-citationSerasinghe, M. N., Wieder, S. Y., Renault, T. T., Elkholi, R., Asciolla, J. J., Yao, J. L., Jabado, O., Hoehn, K. L., Kageyama, Y., Sesaki, H., et al. (2015) · Molecular Cell · doi:10.1016/j.molcel.2015.01.003 · Cited by 388 · see citing works
Wolpin, B. M., Rubinson, D. A., Wang, X., Chan, J. A.-W., Cleary, J. M., Enzinger, P. C., Fuchs, C. S., McCleary, N. J., Meyerhardt, J. A., Ng, K., et al. (2014) · The Oncologist · doi:10.1634/theoncologist.2014-0086 · Cited by 374 · see citing works
Self-citationPetherick, K. J., Conway, O. J. L., Mpamhanga, C., Osborne, S. A., Kamal, A. M., SAXTY, B. A., & Ganley, I. G. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.c114.627778 · Cited by 370 · see citing works
Rojansky, R. B., Cha, M.-Y., & Chan, D. C. (2016) · eLife · doi:10.7554/elife.17896 · Cited by 337 · see citing works
PLIC proteins or ubiquilins regulate autophagy‐dependent cell survival during nutrient starvation
N'Diaye, E., Kajihara, K. K., Hsieh, I., Morisaki, H., Debnath, J., & Brown, E. J. (2009) · The EMBO Reports · doi:10.1038/embor.2008.238 · Cited by 323 · see citing works
High Precision Isotope Ratio Monitoring Techniques in Mass Spectrometry
Brand, W. A. (1996) · Journal of Mass Spectrometry · doi:10.1002/(sici)1096-9888(199603)31:3 · Cited by 299 · see citing works
Ryan, D. P., Hong, T. S., & Bardeesy, N. M. (2014) · New England Journal of Medicine · doi:10.1056/nejmc1412266 · Cited by 291 · see citing works
IsoCor: correcting MS data in isotope labeling experiments
Millard, P., Létisse, F., Sokol, S., & Portais, J. (2012) · Bioinformatics · doi:10.1093/bioinformatics/bts127 · Cited by 278 · see citing works
Hayes, T. K., Neel, N. F., Hu, C., Gautam, P., Chénard, M., Long, B. J., Aziz, M., Kassner, M., Bryant, K. L., Pierobon, M., et al. (2015) · Cancer Cell · doi:10.1016/j.ccell.2015.11.011 · Cited by 266 · see citing works
Self-citationGarrido‐Laguna, I., Uson, M. L., Rajeshkumar, N. V., Tan, A. C., Oliveira, E. D., Karikari, C. A., Villaroel, M. C., Salomon, A., Taylor, G., Sharma, R. B., et al. (2011) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-11-0341 · Cited by 247 · see citing works
Boone, B. A., Bahary, N., Zureikat, A. H., Moser, A. J., Normolle, D. P., Wu, W.-C., Singhi, A. D., Bao, P., Bartlett, D. L., Liotta, L. A., et al. (2015) · Annals of Surgical Oncology · doi:10.1245/s10434-015-4566-4 · Cited by 234 · see citing works
Determining the macropinocytic index of cells through a quantitative image-based assay
Commisso, C., Flinn, R. J., & Bar‐Sagi, D. (2014) · Nature Protocols · doi:10.1038/nprot.2014.004 · Cited by 222 · see citing works
Metabolic Dependencies in RAS -Driven Cancers
Kimmelman, A. C. (2015) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-14-2425 · Cited by 220 · see citing works
Self-citationCampbell, P. M., Groehler, A. L., Lee, K. M., Ouellette, M. M., Khazak, V., & Der, C. J. (2007) · Cancer Research · doi:10.1158/0008-5472.can-06-3752 · Cited by 215 · see citing works
Self-citationActivation Mechanism of Oncogenic Deletion Mutations in BRAF, EGFR, and HER2
Foster, S. A., Whalen, D. M., Özen, A., Wongchenko, M. J., Yin, J., Yen, I., Schaefer, G., Mayfield, J. D., Chmielecki, J., Stephens, P. J., et al. (2016) · Cancer Cell · doi:10.1016/j.ccell.2016.02.010 · Cited by 215 · see citing works
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Guo, J. Y., & White, E. (2016) · Cold Spring Harbor Symposia on Quantitative Biology · doi:10.1101/sqb.2016.81.030981 · Cited by 182 · see citing works
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Vaseva, A. V., Blake, D. R., Gilbert, T. S. K., Ng, S., Hostetter, G. H., Azam, S. H., Ozkan‐Dagliyan, I., Gautam, P., Bryant, K. L., Pearce, K. H., et al. (2018) · Cancer Cell · doi:10.1016/j.ccell.2018.10.001 · Cited by 181 · see citing works
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White, E. (2013) · Genes & Development · doi:10.1101/gad.228122.113 · Cited by 177 · see citing works
Chen, S.-H., Zhang, Y., Van Horn, R. D., Yin, T., Buchanan, S., Yadav, V., Mochalkin, I., Wong, S. S., Yue, Y. G., Huber, L., et al. (2016) · Cancer Discovery · doi:10.1158/2159-8290.cd-15-0896 · Cited by 171 · see citing works
Self-citationMoschos, S. J., Sullivan, R. J., Hwu, W., Ramanathan, R. K., Adjei, A. A., Fong, P. C. C., Shapira‐Frommer, R., Tawbi, H. A.-H., Rubino, J., Rush, T. S., et al. (2018) · JCI Insight · doi:10.1172/jci.insight.92352 · Cited by 151 · see citing works
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Pierobon, M., Ramos, C., Wong, S., Hodge, K. A., Aldrich, J., Byron, S. A., Anthony, S. P., Robert, N. J., Northfelt, D., Jahanzeb, M., et al. (2017) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-16-2656 · Cited by 98 · see citing works
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Baldelli, E., Calvert, V. S., Hodge, A., VanMeter, A., Petricoin, E. F., & Pierobon, M. (2017) · Methods in molecular biology · doi:10.1007/978-1-4939-6990-6_11 · Cited by 96 · see citing works
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Signore, M., Manganelli, V., & Hodge, A. (2017) · Methods in molecular biology · doi:10.1007/978-1-4939-6990-6_4 · Cited by 84 · see citing works
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TOMCIK, K. A., Ibarra, R., Sadhukhan, S., et al. (2010) · Analytical Biochemistry · doi:10.1016/j.ab.2010.11.030 · Cited by 62 · see citing works
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Sanduja, S., Feng, Y., Mathis, R. A., Sokol, E. S., Reinhardt, F., Halaban, R., & Gupta, P. B. (2016) · Oncogene · doi:10.1038/onc.2016.70 · Cited by 58 · see citing works
Lee, D. Y., Teng, A., Pedersen, R. C., Tavangari, F. R., Attaluri, V., McLemore, E. C., Stern, S. L., Bilchik, A. J., & Goldfarb, M. R. (2016) · Annals of Surgical Oncology · doi:10.1245/s10434-016-5626-0 · Cited by 54 · see citing works
Tech, K., Tikunov, A. P., Farooq, H., Morrissy, A. S., Meidinger, J., Fish, T., Green, S. C., Liu, H., Li, Y., Mungall, A. J. J., et al. (2017) · Cancer Research · doi:10.1158/0008-5472.can-16-3304 · Cited by 52 · see citing works
Self-citationFederici, G., Gao, X., Sławek, J., Arodź, T., Shitaye, A., Wulfkuhle, J. D., Maria, R. D., Liotta, L. A., & Petricoin, E. F. (2013) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-12-0690 · Cited by 47 · see citing works
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Signore, M., & Reeder, K. A. (2011) · Methods in molecular biology · doi:10.1007/978-1-60327-216-2_10 · Cited by 42 · see citing works
Baldelli, E., Bellezza, G., Haura, E. B., Crinò, L., Cress, W. D., Deng, J., Ludovini, V., Sidoni, A., Schabath, M. B., Puma, F., et al. (2015) · Oncotarget · doi:10.18632/oncotarget.5941 · Cited by 35 · see citing works
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Shestov, A. A., Lee, S., Nath, K., Guo, L., NELSON, D. S., Roman, J. C., Leeper, D. B., Wasik, M. A., Blair, I. A., & Glickson, J. D. (2016) · Frontiers in Oncology · doi:10.3389/fonc.2016.00135 · Cited by 28 · see citing works
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Geary, M. (2013) · Annals of Surgical Oncology · doi:10.1245/s10434-013-2877-x · Cited by 18 · see citing works
Hypoxia-Induced Metabolomic Alterations in Pancreatic Cancer Cells
Gunda, V., Kumar, S., Dasgupta, A., et al. (2018) · Methods in molecular biology · doi:10.1007/978-1-4939-7665-2_9 · Cited by 16 · see citing works
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(2019) · Annals of Surgical Oncology · doi:10.1245/s10434-019-07174-5 · Cited by 5 · see citing works
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Klionsky, D. J., Abdel-Aziz, A. K., Abdelfatah, S., Abdellatif, M., Abdoli, A., Abel, S., Abeliovich, H., Abildgaard, M. H., Abudu, Y. P., Acevedo-Arozena, A., et al. (2021) · Autophagy · doi:10.1080/15548627.2020.1797280 · Cited by 2,622 · see citing works
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Klionsky, D. J., Petroni, G., Amaravadi, R. K., Baehrecke, E. H., Ballabio, A., Boya, P., Bravo‐San Pedro, J. M., Cadwell, K., Cecconi, F., Choi, A. M. K., et al. (2021) · The EMBO Journal · doi:10.15252/embj.2021108863 · Cited by 1,585 · see citing works
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Moore, A. R., Rosenberg, S. C., McCormick, F., & Malek, S. (2020) · Nature Reviews Drug Discovery · doi:10.1038/s41573-020-0068-6 · Cited by 1,103 · see citing works
Kinsey, C. G., Camolotto, S. A., Boespflug, A. M., Guillen, K. P., Foth, M., Truong, A., Schuman, S. S., Shea, J. E., Seipp, M. T., Yap, J. T., et al. (2019) · Nature Medicine · doi:10.1038/s41591-019-0367-9 · Cited by 634 · see citing works
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Drosten, M., & Barbacid, M. (2020) · Cancer Cell · doi:10.1016/j.ccell.2020.03.013 · Cited by 512 · see citing works
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Uhrig, S., Ellermann, J., Walther, T., Burkhardt, P., Fröhlich, M., Hutter, B., Toprak, U. H., Neumann, O., Stenzinger, A., Scholl, C., et al. (2021) · Genome Research · doi:10.1101/gr.257246.119 · Cited by 526 · see citing works
Wang, S., Zheng, Y., Yang, F., Zhu, L., Zhu, X.-Q., Wang, Z.-F., Wu, X.-L., Zhou, C.-H., Yan, J.-Y., Hu, B.-Y., et al. (2021) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-021-00659-4 · Cited by 369 · see citing works
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Song, Y., Bi, Z., Liu, Y., Qin, F., Wei, Y., & Wei, X. (2023) · Genes & Diseases · doi:10.1016/j.gendis.2022.05.006 · Cited by 212 · see citing works
Combination Therapies with CDK4/6 Inhibitors to Treat <i>KRAS-</i> Mutant Pancreatic Cancer
Goodwin, C. M., Waters, A. M., Klomp, J. E., Javaid, S., Bryant, K. L., Stalnecker, C. A., Drizyte-Miller, K., Papke, B., Yang, R., Amparo, A. M., et al. (2023) · Cancer Research · doi:10.1158/0008-5472.can-22-0391 · Cited by 168 · see citing works
Self-citationNew Horizons in KRAS-Mutant Lung Cancer: Dawn After Darkness
Yang, H., Liang, S.-Q., Schmid, R. A., & Peng, R.-W. (2019) · Frontiers in Oncology · doi:10.3389/fonc.2019.00953 · Cited by 129 · see citing works
Brown, W. S., McDonald, P. C., Nemirovsky, O., Awrey, S., Chafe, S. C., Schaeffer, D. F., Li, J., Renouf, D. J., Stanger, B. Z., & Dedhar, S. (2020) · Cell Reports Medicine · doi:10.1016/j.xcrm.2020.100131 · Cited by 111 · see citing works
TEAD Inhibition Overcomes YAP1/TAZ-Driven Primary and Acquired Resistance to KRASG12C Inhibitors
Edwards, A. C., Stalnecker, C. A., Jean Morales, A., Taylor, K. E., Klomp, J. E., Klomp, J. A., Waters, A. M., Sudhakar, N., Hallin, J., Tang, T. T., et al. (2023) · Cancer Research · doi:10.1158/0008-5472.can-23-2994 · Cited by 91 · see citing works
Self-citationRAS, wanted dead or alive: Advances in targeting RAS mutant cancers
Stalnecker, C. A., & Der, C. J. (2020) · Science Signaling · doi:10.1126/scisignal.aay6013 · Cited by 90 · see citing works
Self-citationRavichandran, M., Hu, J., Cai, C., Ward, N. P., Venida, A., Foakes, C., Kuljanin, M., Yang, A., Hennessey, C. J., Yang, Y., et al. (2022) · Cancer Discovery · doi:10.1158/2159-8290.cd-22-0044 · Cited by 80 · see citing works
Santana-Codina, N., Chandhoke, A. S., Yu, Q., Małachowska, B., Kuljanin, M., Gikandi, A., Stańczak, M., Gableske, S., Jedrychowski, M. P., Scott, D. A., et al. (2020) · Cell Reports · doi:10.1016/j.celrep.2020.03.021 · Cited by 77 · see citing works
Mutations of p53 associated with pancreatic cancer and therapeutic implications
Voutsadakis, I. A. (2021) · Annals of Hepato-Biliary-Pancreatic Surgery · doi:10.14701/ahbps.2021.25.3.315 · Cited by 75 · see citing works
McCubrey, J. A., Yang, L. V., Abrams, S. L., Steelman, L. S., Follo, M. Y., Cocco, L., Ratti, S., Martelli, A. M., Augello, G., & Cervello, M. (2022) · Cells · doi:10.3390/cells11142155 · Cited by 49 · see citing works
Targeting Glucose Metabolism Sensitizes Pancreatic Cancer to MEK Inhibition
Yan, L., Tu, B., Yao, J., Gong, J., Carugo, A., Bristow, C. A., Wang, Q., Zhu, C., Dai, B., Kang, Y., et al. (2021) · Cancer Research · doi:10.1158/0008-5472.can-20-3792 · Cited by 48 · see citing works
Self-citationTargeting eIF4A-Dependent Translation of KRAS Signaling Molecules
Singh, K., Lin, J., Lecomte, N., Mohan, P., Gokce, A., Sanghvi, V. R., Jiang, M., Grbovic-Huezo, O., Burčul, A., Stark, S. G., et al. (2021) · Cancer Research · doi:10.1158/0008-5472.can-20-2929 · Cited by 39 · see citing works
Frank, K. J., Mulero-Sánchez, A., Berninger, A., Ruiz-Cañas, L., Bosma, A., Görgülü, K., Wu, N., Diakopoulos, K. N., Kaya-Aksoy, E., Ruess, D. A., et al. (2022) · Cell Reports Medicine · doi:10.1016/j.xcrm.2022.100815 · Cited by 40 · see citing works
Targeting autophagy as a therapeutic strategy against pancreatic cancer
Yamamoto, K., Iwadate, D., Kato, H., Nakai, Y., Tateishi, K., & Fujishiro, M. (2022) · Journal of Gastroenterology · doi:10.1007/s00535-022-01889-1 · Cited by 29 · see citing works
Hanada, K., Kawada, K., Nishikawa, G., Toda, K., Maekawa, H., Nishikawa, Y., Masui, H., Hirata, W., Okamoto, M., Kiyasu, Y., et al. (2021) · Cancer Letters · doi:10.1016/j.canlet.2021.09.023 · Cited by 27 · 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
- Authors
- Bryant, K. L., Stalnecker, C. A., Zeitouni, D., Klomp, J. E., Peng, S., Tikunov, A. P., Gunda, V., Pierobon, M., Waters, A. M., George, S. D., Tomar, G., Papke, B., Hobbs, G. A., Yan, L., Hayes, T. K., Diehl, J. N., Goode, G. D., Chaika, N. V., Wang, Y., Zhang, G.-F., Witkiewicz, A. K., Knudsen, E. S., Petricoin, E. F., Singh, P. K., Macdonald, J. M., Tran, N. L., Lyssiotis, C. A., Ying, H., Kimmelman, A. C., Cox, A. D., & Der, C. J.
- Affiliations
- University of North Carolina at Chapel Hill (US)
- Translational Genomics Research Institute (US)
- University of Nebraska Medical Center (US)
- George Mason University (US)
- Duke University (US)
- Roswell Park Comprehensive Cancer Center (US)
- Mayo Clinic (US)
- University of Michigan (US)
- The University of Texas MD Anderson Cancer Center (US)
- NYU Langone Health (US)
- Corresponding author
- Der, Channing J.
- ORCID
- Bryant, Kirsten L.
- Stalnecker, Clint A.
- Zeitouni, Daniel
- Klomp, Jennifer E.
- Tikunov, Andrey P.
- Gunda, Venugopal
- Pierobon, Mariaelena
- Waters, Andrew M.
- George, Samuel D.
- Papke, Björn
- Hobbs, G. Aaron
- Hayes, Tikvah K.
- Diehl, J. Nathaniel
- Chaika, Nina V.
- Wang, Yingxue
- Witkiewicz, Agnieszka K.
- Knudsen, Erik S.
- Petricoin, Emanuel F.
- Singh, Pankaj K.
- Tran, Nhan L.
- Lyssiotis, Costas A.
- Ying, Haoqiang
- Kimmelman, Alec C.
- Cox, Adrienne D.
- Der, Channing J.
- Venue
- Nature Medicine
- Published
- 2019-03-04
- Volume
- 25
- Issue
- 4
- Pages
- 628-640
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC6484853
- OpenAlex
- W2920097475
- Cited by
- 692
- References
- 65
- Citations by year
- 2026: 42 · 2025: 56 · 2024: 103 · 2023: 100 · 2022: 116 · 2021: 132 · 2020: 98 · 2019: 43 · 2018: 1
- FWCI
- 77.23
- Type
- journal article
- Language
- en
- Update notices
- correction (2020-06-01)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- UNC Libraries
- Funders
- U.S. Department of Defense (W81XWH-15–1-, W81XWH, CA210439, P30CA016672, W81XWH1510611)
- American Association for Cancer Research (15-90-25-DER, P30CA016672)
- American Cancer Society
- Pancreatic Cancer Action Network (15-90-25-DER)
- Lustgarten Foundation
- Deutsche Forschungsgemeinschaft (PF-18-061, DFG PA 3051/1-1, PA 3051/1-1)
- National Institutes of Health (5r01ca042978-30, W81XWH, CA016086, R01CA42978)
- University of Texas MD Anderson Cancer Center (P30-CA-016672, RSG-13-298-01-TBG)
- National Cancer Institute (F32CA200313, R01CA42978, R01CA163649, P01CA203657, R01CA175747, R01CA210439, CA016086, R35CA232113, T32CA009156, P50CA196510, F32CA239328, R01-CA042978, CA163649, R01CA188048, P50CA127297, F32CA232529, R01CA216853, R35CA232124, U01CA199235, CA216853, F30CA243253, R01CA157490, CA210439, P30CA016672, P01CA117969, P30CA036727, P30CA016086, T32CA071341)
- National Institute of General Medical Sciences (R01GM095567)
- National Institute of Environmental Health Sciences (P30ES010126)
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill (CA016086, P30-CA016086)
- Congressionally Directed Medical Research Programs
- Topics
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- pancreatic ductal adenocarcinoma, KRAS, autophagy, autophagic flux, chloroquine, combination therapy, cancer metabolism, glycolysis, mitochondrial function
- MeSH terms
- Animals, Autophagy, Chloroquine, Drug Synergism, Humans, Mitochondria, Mutation, Pancreatic Neoplasms, Proto-Oncogene Proteins p21(ras), MAP Kinase Signaling System, Cell Line, Tumor, Protein Kinase Inhibitors, Cell Proliferation, Mice, HEK293 Cells
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