Extensive preclinical validation of combined RMC-4550 and LY3214996 supports clinical investigation for KRAS mutant pancreatic cancer
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Over 90% of pancreatic cancers present mutations in KRAS, one of the most common oncogenic drivers overall. Currently, most KRAS mutant isoforms cannot be targeted directly. Moreover, targeting single RAS downstream effectors induces adaptive resistance mechanisms. We report here on the combined inhibition of SHP2, upstream of KRAS, using the allosteric inhibitor RMC-4550 and of ERK, downstream of KRAS, using LY3214996. This combination shows synergistic anti-cancer activity in vitro , superior disruption of the MAPK pathway, and increased apoptosis induction compared with single-agent treatments. In vivo , we demonstrate good tolerability and efficacy of the combination, with significant tumor regression in multiple pancreatic ductal adenocarcinoma (PDAC) mouse models. Finally, we show evidence that 18 F-fluorodeoxyglucose (FDG) positron emission tomography (PET) can be used to assess early drug responses in animal models. Based on these results, we will investigate this drug combination in the SHP2 and ERK inhibition in pancreatic cancer (SHERPA; ClinicalTrials.gov: NCT04916236) clinical trial, enrolling patients with KRAS -mutant PDAC.
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RMC-4550 inhibits the growth of multiple subtypes of lung, melanoma, colorectal, and pancreatic cancer cells.
“Furthermore, RMC-4550 inhibits the growth of multiple subtypes of lung, melanoma, colorectal, and pancreatic cancer cells.290,291”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [290]
RMC-4550 reduces oncogenic RAS/RAF/MEK/ERK signaling and cancer growth by disrupting SOS1-mediated RAS-GTP.
“RMC-4550 reduces oncogenic RAS/RAF/MEK/ERK signaling and cancer growth by disrupting SOS1-mediated RAS-GTP.”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [290]
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Siegel, R. L., Miller, K. D., & Jemal, A. (2020) · CA: A Cancer Journal for Clinicians · doi:10.3322/caac.21590 · Cited by 20,444 · see citing works
Drug combination studies and their synergy quantification using the Chou-Talalay method
Chou, T.-C. (2010) · Cancer Research · doi:10.1158/0008-5472.can-09-1947 · Cited by 5,739 · see citing works
Whole genomes redefine the mutational landscape of pancreatic cancer
Initiative, A. P. C. G., Waddell, N., Pajic, M., Patch, A.-M., Chang, D. K., Kassahn, K. S., Bailey, P., Johns, A. L., Miller, D., Nones, K., et al. (2015) · Nature · doi:10.1038/nature14169 · Cited by 2,642 · see citing works
Hingorani, S. R., Wang, L., Multani, A. S., Combs, C., Deramaudt, T. B., Hruban, R. H., Rustgi, A. K., Chang, S., & Tuveson, D. A. (2005) · Cancer Cell · doi:10.1016/j.ccr.2005.04.023 · Cited by 2,609 · see citing works
Mizrahi, J. D., Surana, R., Valle, J. W., & Shroff, R. T. (2020) · The Lancet · doi:10.1016/s0140-6736(20)30974-0 · Cited by 2,559 · see citing works
Maintenance Olaparib for Germline <i>BRCA</i> -Mutated Metastatic Pancreatic Cancer
Golan, T., Hammel, P., Reni, M., Van Cutsem, E., Macarulla, T., Hall, M. J., Park, J.-O., Hochhauser, D., Arnold, D., Oh, D.-Y., et al. (2019) · New England Journal of Medicine · doi:10.1056/nejmoa1903387 · Cited by 2,302 · see citing works
Self-citationOncogenic 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
Analysis of lung tumor initiation and progression using conditional expression of oncogenic K-rasPreprint
Jackson, E. L., Willis, N. A., Mercer, K. L., Bronson, R. T., Crowley, D. G., Montoya, R., Jacks, T., & Tuveson, D. A. (2001) · Genes & Development · doi:10.1101/gad.943001 · Cited by 1,877 · see citing works
KRAS <sup>G12C</sup> Inhibition with Sotorasib in Advanced Solid Tumors
Hong, D. S., Fakih, M. G., Strickler, J. H., Desai, J., Durm, G. A., Shapiro, G. I., Falchook, G. S., Price, T. J., Sacher, A., Denlinger, C. S., et al. (2020) · New England Journal of Medicine · doi:10.1056/nejmoa1917239 · Cited by 1,733 · 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
Hallin, J., Engstrom, L. D., Hargis, L., Calinisan, A., Aranda, R., Briere, D. M., Sudhakar, N., Bowcut, V., Baer, B. R., Ballard, J. A., et al. (2020) · Cancer Discovery · doi:10.1158/2159-8290.cd-19-1167 · Cited by 1,304 · see citing works
The ‘Shp'ing news: SH2 domain-containing tyrosine phosphatases in cell signaling
Neel, B. G., Gu, H., & Pao, L. (2003) · Trends in Biochemical Sciences · doi:10.1016/s0968-0004(03)00091-4 · Cited by 1,249 · see citing works
Whole-exome sequencing of pancreatic cancer defines genetic diversity and therapeutic targets
Witkiewicz, A. K., McMillan, E. A., Balaji, U., Baek, G., Lin, W.-C., Mansour, J., Mollaee, M., Wagner, K.-U., Koduru, P., Yopp, A., et al. (2015) · Nature Communications · doi:10.1038/ncomms7744 · Cited by 1,115 · see citing works
Acquired Resistance to Immune Checkpoint Inhibitors
Schoenfeld, A. J., & Hellmann, M. D. (2020) · Cancer Cell · doi:10.1016/j.ccell.2020.03.017 · Cited by 975 · see citing works
Marino, S., Vooijs, M., van der Gulden, H., Jonkers, J., & Berns, A. (2000) · Genes & Development · doi:10.1101/gad.14.8.994 · Cited by 920 · 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
Dose Escalation Methods in Phase I Cancer Clinical Trials
Le Tourneau, C., Lee, J. J., & Siu, L. L. (2009) · JNCI: Journal of the National Cancer Institute · doi:10.1093/jnci/djp079 · Cited by 867 · see citing works
Lesina, M., Kurkowski, M. U., Ludes, K., Rose-John, S., Treiber, M., Klöppel, G., Yoshimura, A., Reindl, W., Sipos, B., Akira, S., et al. (2011) · Cancer Cell · doi:10.1016/j.ccr.2011.03.009 · Cited by 862 · see citing works
Self-citationJuneja, V. R., McGuire, K. A., Manguso, R. T., LaFleur, M. W., Collins, N. B., Haining, W. N., Freeman, G. J., & Sharpe, A. H. (2017) · The Journal of Experimental Medicine · doi:10.1084/jem.20160801 · Cited by 848 · 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
RAS Interaction with PI3K: More Than Just Another Effector Pathway
Castellano, E., & Downward, J. (2011) · Genes & Cancer · doi:10.1177/1947601911408079 · Cited by 762 · see citing works
Combination of ERK and autophagy inhibition as a treatment approach for pancreatic cancer
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., et al. (2019) · Nature Medicine · doi:10.1038/s41591-019-0368-8 · Cited by 692 · see citing works
Direct small-molecule inhibitors of KRAS: from structural insights to mechanism-based design
Ostrem, J. M. L., & Shokat, K. M. (2016) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2016.139 · Cited by 641 · see citing works
Stromal biology and therapy in pancreatic cancer: a changing paradigm
Neeße, A., Algül, H., Tuveson, D. A., & Gress, T. M. (2015) · Gut · doi:10.1136/gutjnl-2015-309304 · Cited by 561 · see citing works
Self-citationPishvaian, M. J., Blais, E. M., Brody, J. R., Lyons, E. E., DeArbeloa, P., Hendifar, A. E., Mikhail, S., Chung, V. M., Sahai, V., Sohal, D. P. S., et al. (2020) · The Lancet Oncology · doi:10.1016/s1470-2045(20)30074-7 · Cited by 548 · see citing works
Targeting the MAPK pathway in KRAS-driven tumors
Drosten, M., & Barbacid, M. (2020) · Cancer Cell · doi:10.1016/j.ccell.2020.03.013 · Cited by 512 · see citing works
Broadening the Impact of Immunotherapy to Pancreatic Cancer: Challenges and Opportunities
Balachandran, V. P., Beatty, G. L., & Dougan, S. K. (2019) · Gastroenterology · doi:10.1053/j.gastro.2018.12.038 · Cited by 444 · see citing works
Hofmann, M. H., Gmachl, M., Ramharter, J., Savarese, F., Gerlach, D., Marszalek, J. R., Sanderson, M. P., Kessler, D., Trapani, F., Arnhof, H., et al. (2021) · Cancer Discovery · doi:10.1158/2159-8290.cd-20-0142 · Cited by 444 · see citing works
Nichols, R. J., Haderk, F., Stahlhut, C., Schulze, C. J., Hemmati, G., Wildes, D., Tzitzilonis, C., Mordec, K., Marquez, A., Romero, J., et al. (2018) · Nature Cell Biology · doi:10.1038/s41556-018-0169-1 · Cited by 415 · see citing works
A combinatorial strategy for treating KRAS-mutant lung cancer
Manchado, E., Weissmueller, S., Morris, J. P., Chen, C.-C., Wullenkord, R., Lujambio, A., de Stanchina, E., Poirier, J. T., Gainor, J. F., Corcoran, R. B., et al. (2016) · Nature · doi:10.1038/nature18600 · Cited by 403 · see citing works
From state-of-the-art treatments to novel therapies for advanced-stage pancreatic cancer
Nevala-Plagemann, C., Hidalgo, M. M., & Garrido‐Laguna, I. (2019) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-019-0281-6 · Cited by 391 · see citing works
Mutant KRAS-driven cancers depend on PTPN11/SHP2 phosphatase
Ruess, D. A., Heynen, G. J., Ciecielski, K. J., Ai, J., Berninger, A., Kabacaoglu, D., Görgülü, K., Dantes, Z., Wörmann, S. M., Diakopoulos, K. N., et al. (2018) · Nature Medicine · doi:10.1038/s41591-018-0024-8 · Cited by 370 · cited 3× · see citing works
“Combinatorial effect in vitro In a previous study, we showed promising in vitro and in vivo results to support combined SHP2 andMEK inhibition for the treatment of pancreatic cancer.(23,24) While the reported combinatorial strategy is sound, the frequently observed side effects and the common occurrence of resistance…”
BackgroundResultInfluentialSelf-citationInfante, J. R., Somer, B. G., Park, J. O., Li, C., Scheulen, M. E., Kasubhai, S. M., Oh, D., Liu, Y., Redhu, S., Steplewski, K. M., et al. (2014) · European Journal of Cancer · doi:10.1016/j.ejca.2014.04.024 · Cited by 365 · see citing works
The molecular functions of Shp2 in the Ras/Mitogen-activated protein kinase (ERK1/2) pathway
Dance, M., Montagner, A., Salles, J.-P., Yart, A., & Raynal, P. (2008) · Cellular Signalling · doi:10.1016/j.cellsig.2007.10.002 · Cited by 361 · see citing works
Management of BRAF and MEK inhibitor toxicities in patients with metastatic melanoma
Welsh, S. J., & Corrie, P. G. (2015) · Therapeutic Advances in Medical Oncology · doi:10.1177/1758834014566428 · Cited by 341 · see citing works
Jänne, P. A., van den Heuvel, M. M., Barlesi, F., Cobo, M., Mazieres, J., Crinò, L., Orlov, S., Blackhall, F., Wolf, J., Garrido, P., et al. (2017) · JAMA · doi:10.1001/jama.2017.3438 · Cited by 335 · see citing works
SHP2 is required for growth of KRAS-mutant non-small-cell lung cancer in vivo
Mainardi, S., Mulero-Sánchez, A., Prahallad, A., Germano, G., Bosma, A., Krimpenfort, P., Lieftink, C., Steinberg, J. D., de Wit, N., Gonçalves-Ribeiro, S., et al. (2018) · Nature Medicine · doi:10.1038/s41591-018-0023-9 · Cited by 320 · see citing works
Self-citationMechanism of MEK inhibition determines efficacy in mutant KRAS- versus BRAF-driven cancers
Hatzivassiliou, G., Haling, J. R., Chen, H., Song, K. W., Price, S., Heald, R. A., Hewitt, J. F. M., Zak, M., Peck, A., Orr, C., et al. (2013) · Nature · doi:10.1038/nature12441 · Cited by 317 · see citing works
Sun, C., Hobor, S., Bertotti, A., Zecchin, D., Huang, S., Galimi, F., Cottino, F., Prahallad, A., Grernrum, W., Tzani, A., et al. (2014) · Cell Reports · doi:10.1016/j.celrep.2014.02.045 · Cited by 304 · see citing works
Self-citationGarcia Fortanet, J., Chen, C. H.-T., Chen, Y.-N. P., Chen, Z., Deng, Z., Firestone, B., Fekkes, P., Fodor, M., Fortin, P. D., Fridrich, C., et al. (2016) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.6b00680 · Cited by 298 · 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
Targeting wild-type KRAS-amplified gastroesophageal cancer through combined MEK and SHP2 inhibition
Wong, G. S., Zhou, J., Liu, J. B., Wu, Z., Xu, X., Li, T., Xu, D., Schumacher, S. E., Puschhof, J., McFarland, J., et al. (2018) · Nature Medicine · doi:10.1038/s41591-018-0022-x · Cited by 266 · see citing works
Pishvaian, M. J., Bender, R. J., Halverson, D., Rahib, L., Hendifar, A. E., Mikhail, S., Chung, V., Picozzi, V. J., Sohal, D., Blais, E. M., et al. (2018) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-18-0531 · Cited by 245 · see citing works
Doehn, U., Hauge, C., Frank, S. R., Jensen, C. J., Duda, K., Nielsen, J. V., Cohen, M. S., Johansen, J. V., Winther, B. R., Lund, L. R., et al. (2009) · Molecular Cell · doi:10.1016/j.molcel.2009.08.002 · Cited by 228 · see citing works
Nakhai, H., Sel, S., Favor, J., Mendoza-Torres, L., Paulsen, F., Duncker, G. I. W., & Schmid, R. (2007) · Development · doi:10.1242/dev.02781 · Cited by 219 · see citing works
Su, 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-citationSHP2 inhibition triggers anti-tumor immunity and synergizes with PD-1 blockade
Zhao, M., Guo, W., Wu, Y., Yang, C., Zhong, L., Deng, G., Zhu, Y., Liu, W., Gu, Y., Lu, Y., et al. (2019) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2018.08.009 · Cited by 190 · see citing works
Wagle, M.-C., Kirouac, D. C., Klijn, C. N., Liu, B., Mahajan, S., Junttila, M. R., Moffat, J. G., Merchant, M. A., Huw, L. Y., Wongchenko, M. J., et al. (2018) · npj Precision Oncology · doi:10.1038/s41698-018-0051-4 · Cited by 189 · see citing works
European cancer mortality predictions for the year 2020 with a focus on prostate cancer
Carioli, G., Bertuccio, P., Boffetta, P., Levi, F., Vecchia, C. L., Negri, E., & Malvezzi, M. (2020) · Annals of Oncology · doi:10.1016/j.annonc.2020.02.009 · Cited by 171 · see citing works
Iacobuzio–Donahue, C. A., Velculescu, V. E., Wolfgang, C. L., & Hruban, R. H. (2012) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-12-0315 · Cited by 149 · see citing works
Jänne, P. A., Rybkin, I. I., Spira, A. I., Riely, G. J., Papadopoulos, K. P., Sabari, J. K., Johnson, M. L., Heist, R. S., Bazhenova, L., Barve, M., et al. (2020) · European Journal of Cancer · doi:10.1016/s0959-8049(20)31076-5 · Cited by 140 · see citing works
Tolcher, A. W., Bendell, J. C., Papadopoulos, K. P., Burris, H. A., Patnaik, A., Jones, S. F., Rasco, D. W., Cox, D. S., Durante, M., Bellew, K. M., et al. (2014) · Annals of Oncology · doi:10.1093/annonc/mdu482 · Cited by 132 · see citing works
Targeting RAS-mutant cancers: is ERK the key?
Ryan, M. B., Der, C., Wang-Gillam, A., & Cox, A. (2015) · Trends in Cancer · doi:10.1016/j.trecan.2015.10.001 · Cited by 125 · see citing works
A Parallel Phase I/II Clinical Trial Design for Combination Therapies
Huang, X., Biswas, S., Oki, Y., Issa, J. J., & Berry, D. A. (2006) · Biometrics · doi:10.1111/j.1541-0420.2006.00685.x · Cited by 116 · see citing works
Bhagwat, S. V., McMillen, W. T., Cai, S., Zhao, B., Whitesell, M., Shen, W., Kindler, L. J., Flack, R. S., Wu, W., Anderson, B. D., et al. (2019) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-19-0183 · Cited by 112 · see citing works
Quintana, E., Schulze, C. J., Myers, D. R., Choy, T. J., Mordec, K., Wildes, D. P., Shifrin, N. T., Belwafa, A., Koltun, E. S., Gill, A. L., et al. (2020) · Cancer Research · doi:10.1158/0008-5472.can-19-3038 · Cited by 98 · see citing works
Stroma-Targeting Therapy in Pancreatic Cancer: One Coin With Two Sides?
Jiang, B., Zhou, L., Lü, J., Wang, Y., Liu, C., You, L., & Guo, J. (2020) · Frontiers in Oncology · doi:10.3389/fonc.2020.576399 · Cited by 96 · see citing works
Johnson, M. L., Ou, S. H. I., Barve, M., Rybkin, I. I., Papadopoulos, K. P., Leal, T. A., Velastegui, K., Christensen, J. G., Kheoh, T., Chao, R. C., et al. (2020) · European Journal of Cancer · doi:10.1016/s0959-8049(20)31077-7 · Cited by 77 · see citing works
D’Errico, G., Alonso‐Nocelo, M., Vallespinós, M., Hermann, P. C., Alcalá, S., Pedrero, C., Martín-Hijano, L., Valle, S., Earl, J., Cassiano, C., et al. (2019) · Oncogene · doi:10.1038/s41388-019-0803-9 · Cited by 75 · see citing works
A bright future for KRAS inhibitors
Bar-Sagi, D., Knelson, E. H., & Sequist, L. V. (2020) · Nature Cancer · doi:10.1038/s43018-019-0016-8 · Cited by 74 · see citing works
Tumor Intrinsic Efficacy by SHP2 and RTK Inhibitors in KRAS-Mutant Cancers
Hao, H.-X., Wang, H., Liu, C., Kovats, S., Velazquez, R., Lu, H., Pant, B., Shirley, M., Meyer, M. J., Pu, M., et al. (2019) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-19-0170 · Cited by 53 · see citing works
Early Response Assessment in Pancreatic Ductal Adenocarcinoma Through Integrated PET/MRI
Wang, Z. J., Behr, S. C., Consunji, M., Yeh, B. M., Ohliger, M. A., Gao, K. T., Ko, A. H., Cinar, P., Tempero, M. A., & Collisson, E. A. (2018) · American Journal of Roentgenology · doi:10.2214/ajr.18.19602 · Cited by 42 · see citing works
Liu, Z., Zhao, Y. Q., Fang, J., Cui, R., Xiao, Y., & Xu, Q. (2017) · Oncotarget · doi:10.18632/oncotarget.18591 · Cited by 36 · see citing works
Pass, H. I., Ball, D. S., & Scagliotti, G. V. (2017) · Cited by 29 · see citing works
Kasuga, A., Nakagawa, K., Fumio, N., Shimizu, T., Naruge, D., Nishina, S., Kitamura, H., Kurata, T., Takasu, A., Fujisaka, Y., et al. (2015) · Investigational New Drugs · doi:10.1007/s10637-015-0270-2 · Cited by 19 · see citing works
An Update on Chemical Classes Targeting ERK1/2 for the Management of Cancer
Pathania, S., & Rawal, R. K. (2020) · Future Medicinal Chemistry · doi:10.4155/fmc-2019-0339 · Cited by 14 · see citing works
Management of Toxicities of Targeted Therapies
Yang, J. C., Lin, C.-C., & Chu, C. (2018) · Elsevier eBooks · doi:10.1016/b978-0-323-52357-8.00049-4 · Cited by 4 · see citing works
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Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials
Xie, X., Yu, T., Li, X., Zhang, N., Foster, L. J., Peng, C., Huang, W., & He, G. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01589-z · Cited by 396 · see citing works
SHP2: A Pleiotropic Target at the Interface of Cancer and Its Microenvironment
Sodir, N. M., Pathria, G., Adamkewicz, J. I., Kelley, E. H., Sudhamsu, J., Merchant, M. A., Chiarle, R., & Maddalo, D. (2023) · Cancer Discovery · doi:10.1158/2159-8290.cd-23-0383 · Cited by 103 · see citing works
Combinatorial strategies to target RAS-driven cancers
Perurena, N., Situ, L., & Cichowski, K. M. (2024) · Nature reviews. Cancer · doi:10.1038/s41568-024-00679-6 · Cited by 104 · see citing works
KRAS mutation: The booster of pancreatic ductal adenocarcinoma transformation and progression
Zhang, Z., Zhang, H., Liao, X., & Tsai, H. (2023) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2023.1147676 · Cited by 62 · see citing works
Adamopoulos, C., Cave, D. D., & Papavassiliou, A. G. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25031631 · Cited by 41 · see citing works
The current landscape of using direct inhibitors to target KRASG12C-mutated NSCLC
Batrash, F., Kutmah, M., & Zhang, J. (2023) · Experimental Hematology and Oncology · doi:10.1186/s40164-023-00453-8 · Cited by 40 · see citing works
Targeting KRAS in Colorectal Cancer: A Bench to Bedside Review
Bteich, F., Mohammadi, M., Li, T., Bhat, M. A., Sofianidi, A. A., Wei, N., & Kuang, C. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241512030 · Cited by 32 · see citing works
Tyrosine phosphatase PTPN11/SHP2 in solid tumors - bull’s eye for targeted therapy?
Chen, X., Keller, S. J., Hafner, P., Alrawashdeh, A. Y., Avery, T. Y., Norona, J., Zhou, J., & Ruess, D. A. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1340726 · Cited by 35 · see citing works
Self-citationXiao, H., Wang, A., Wen, S., Qian, Y., Wu, C., Wang, X., Yang, P., Sun, Q., Wang, G., Ouyang, L., et al. (2025) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-025-02169-z · Cited by 22 · see citing works
Nanomedicine and epigenetics: New alliances to increase the odds in pancreatic cancer survival
Urbanova, M., Cihova, M., Buociková, V., Slopovský, J., Dubovan, P., Pinďák, D., Tomáš, M., García‐Bermejo, L., Rodríguez-Garrote, M., Earl, J., et al. (2023) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2023.115179 · Cited by 18 · see citing works
Zhang, J. H., Darman, L., Hassan, M. S., von Holzen, U. W., & Awasthi, N. (2023) · Oncology Reports · doi:10.3892/or.2023.8643 · Cited by 17 · see citing works
Hou, Q., Jiang, W., Li, W., Huang, C., Yang, K., Chen, X., Huang, M., Shu, C., Luo, G., Sun, H., et al. (2023) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.3c00992 · Cited by 16 · see citing works
Contreras, C. T., Falke, J. D., Seifert, D., Schneider, C., Krauß, L., Fang, X., Müller, D., Demirdizen, E., Spitzner, M., Oliveira, T. D., et al. (2024) · Molecular Oncology · doi:10.1002/1878-0261.13725 · Cited by 18 · see citing works
Unveiling the Promise: Navigating Clinical Trials 1978–2024 for PDAC
Dominguez, A. A., Perz, M., Xu, Y., Cedillo, L. G., Huang, O. L., McIntyre, C. A., Vudatha, V., Trevino, J. G., Liu, J., & Wang, P. (2024) · Cancers · doi:10.3390/cancers16213564 · Cited by 16 · see citing works
Rational combination of SHP2 and mTOR inhibition for the treatment of hepatocellular carcinoma
Mulero‐Sánchez, A., Ramirez, C. F. A., du Chatinier, A., Wang, H., Koomen, S. J. I., Song, J., de Groot, M. H. P., Lieftink, C., Bosma, A. R., Burylo, A. M., et al. (2023) · Molecular Oncology · doi:10.1002/1878-0261.13377 · Cited by 14 · see citing works
Self-citationTargeting autophagy drug discovery: Targets, indications and development trends
Jiang, M., Wu, W., Xiong, Z., Ye, Z., Ye, Z., & Wu, Z. (2024) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2023.116117 · Cited by 13 · see citing works
Sharma, J. R., Dubey, A., & Yadav, U. C. S. (2024) · Life Sciences · doi:10.1016/j.lfs.2024.122433 · Cited by 12 · see citing works
Precision Medicine in Pancreatitis: The Future of Acute Pancreatitis Care
Garami, A., & Hegyi, P. J. (2023) · Function · doi:10.1093/function/zqad015 · Cited by 12 · see citing works
Progress in the development of ERK1/2 inhibitors for treating cancer and other diseases
Grogan, L., & Shapiro, P. (2024) · Advances in pharmacology · doi:10.1016/bs.apha.2024.04.001 · Cited by 11 · see citing works
Hafner, P., Keller, S. J., Chen, X., Alrawashdeh, A. Y., Jumaa, H., Nollmann, F. I., Besson, S., Kemming, J., Gorka, O., Das, T., et al. (2026) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-025-02563-7 · Cited by 9 · see citing works
Self-citationSignalling in pancreatic cancer: from pathways to therapy
Zhou, K., Liu, Y., Yuan, S., Zhou, Z., Ji, P., Huang, Q., Wen, F., & Li, Q. (2023) · Journal of drug targeting · doi:10.1080/1061186x.2023.2274806 · Cited by 8 · see citing works
Combined Omipalisib and MAPK Inhibition Suppress PDAC Growth
Bye, B. A., Jack, J. L., Pierce, A., Walsh, R. M., Eades, A. E., Chalise, P., Olou, A. A., & VanSaun, M. N. (2025) · Cancers · doi:10.3390/cancers17071152 · Cited by 7 · see citing works
Puliga, E., Bellis, C. D., Michelina, S. V., Capelôa, T., Migliore, C., Orrù, C., Baiocchi, G. L., Manzoni, G. D., Pietrantonio, F., Reddavid, R., et al. (2024) · Gastric Cancer · doi:10.1007/s10120-024-01468-8 · Cited by 6 · see citing works
Merk, D. J., Tsiami, F., Hirsch, S., Walter, B., Haeusser, L. A., Maile, J. D., Stahl, A., Jarboui, M. A., Lechado‐Terradas, A., Klose, F., et al. (2024) · Genome biology · doi:10.1186/s13059-024-03438-w · Cited by 6 · see citing works
An Aptamer against MNK1 for Non-Small Cell Lung Cancer Treatment
Carrión-Marchante, R., Pinto‐Díez, C., Klett-Mingo, J. I., Palacios, E., Barragán-Usero, M., Pérez-Morgado, M. I., Pascual-Mellado, M., Alcalá, S., Ruíz-Cañas, L., Sáinz, B., et al. (2023) · Pharmaceutics · doi:10.3390/pharmaceutics15041273 · Cited by 6 · see citing works
Maduabuchi, W. O., Tansi, F. L., Heller, R., & Hilger, I. (2023) · Biomedicines · doi:10.3390/biomedicines11082256 · Cited by 5 · see citing works
Zhu, C., Li, L., Yu, Y., Wang, X., Shi, Y., Gao, Y., Chen, K., Liu, X., Cui, Y., Zhang, T., et al. (2024) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2024.117078 · Cited by 5 · see citing works
Moossavi, M., Zhu, P., Ding, Y., Mondaca‐Ruff, D., Yan, F., Ma, X., & Xu, X. (2025) · JACC CardioOncology · doi:10.1016/j.jaccao.2025.08.005 · Cited by 2 · see citing works
KRAS G12C Inhibitors: New Drugs, A New Hope
Singhal, S., Schokrpur, S., Gandara, D. R., & Riess, J. W. (2024) · Journal of Thoracic Oncology · doi:10.1016/j.jtho.2024.09.1383 · Cited by 1 · see citing works
Davoudi, Z., Dexheimer, T. S., Coussens, N. P., Silvers, T. E., Fox, R. G., Kemp, S. B., Juneja, P., Morris, J., Hollingshead, M. G., Takebe, N., et al. (2025) · Cancer Research Communications · doi:10.1158/2767-9764.crc-24-0582 · Cited by 2 · see citing works
Zhu, C., Zhang, Y., Jin, Y., Yu, Y., Zhang, N., Yang, L., Gao, Y., Zhang, M., Shi, Y., Gao, Y., et al. (2026) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.5c03184 · Cited by 1 · see citing works
Wang, S., Zhao, X., Dong, J. X., Zhang, J., Wang, Y., Jin, H., Jiang, X., Chen, L., Zhang, M., Ji, L., et al. (2026) · Journal of Translational Medicine · doi:10.1186/s12967-026-08477-4 · Cited by 1 · see citing works
Davoudi, Z., Dexheimer, T. S., Coussens, N. P., Silvers, T. E., Morris, J., Takebe, N., Doroshow, J. H., & Teicher, B. A. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.11.17.623998 · Cited by 1 · see citing works
Chen, X., Keller, S. J., Das, T., Hafner, P., Alrawashdeh, A. Y., Jumaa, H., Chen, T., Besson, S., Norona, J., Schneider, M., et al. (2025) · medRxiv · doi:10.1101/2025.09.09.25335395
Self-citationSAIMSARA (2026) · SAIMSARA Journal · doi:10.62487/saimsaradc4d1e0f
Zhu, C., Wang, C., Zhu, Y., Yu, Z., Lin, Y., Zhang, Y., Jin, Y., Zhang, N., Liu, X., Ye, X., et al. (2026) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.6c00836
Drugging ERK1/2 in Cancer: A Glimpse of Small‐Molecule Inhibitors
Peng, Z., Fu, Y., Chen, Y., Fan, B., & Liu, B. (2026) · Medicinal Research Reviews · doi:10.1002/med.70084
Alrawashdeh, A. Y., Chen, X., Hafner, P., Keller, S. J., Das, T., Jumaa, H., Avery, T. Y., Besson, S., Hempel, S., Mewes, S., et al. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.05.23.727401
Self-citationShi, H., Komohara, Y., & Yasunaga, M. (2026) · Microbiology and Immunology · doi:10.1111/1348-0421.70099
- Authors
- 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., Kabacaoğlu, D., Schmidt, F., Kohlmann, L., van Tellingen, O., Thijssen, B., van de Ven, M., Proost, N., Kossatz, S., Weber, W. A., Sainz, B., Bernards, R., Algül, H., Lesina, M., & Mainardi, S.
- Affiliations
- TUM Klinikum (DE)
- The Netherlands Cancer Institute (NL)
- University of Freiburg (DE)
- Corresponding author
- Mainardi, Sara
- ORCID
- Venue
- Cell Reports Medicine
- Publisher
- Elsevier BV
- Published
- 2022-11
- Volume
- 3
- Issue
- 11
- Pages
- 100815
- ISSN
- 2666-3791 (ISSN-L)
- PMC
- PMC9729824
- OpenAlex
- W4309331198
- Cited by
- 40
- References
- 67
- Citations by year
- 2026: 8 · 2025: 5 · 2024: 14 · 2023: 13
- FWCI
- 3.35
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports Medicine (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion, cc-by-nc-nd)
- mediaTUM – the media and publications repository of the Technical University Munich (Technical University Munich) (submittedVersion)
- mediaTUM – the media and publications repository of the Technical University Munich (Technical University Munich) (submittedVersion, other-oa)
- Funders
- American Association for Cancer Research
- Lustgarten Foundation (SU2C-AACR-PCC-01-18)
- Topics
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Keywords
- pancreatic ductal adenocarcinoma, LY3214996, ERK inhibitor, combination therapy, MAPK inhibition, apoptosis, FDG-PET, preclinical validation
- MeSH terms
- Animals, Clinical Trials as Topic, Pancreatic Neoplasms, Pyrazoles, Pyrroles, Proto-Oncogene Proteins p21(ras), Carcinoma, Pancreatic Ductal, Cell Line, Tumor, Protein Kinase Inhibitors, Mice
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