Kras oncogene ablation prevents resistance in advanced lung adenocarcinomas
Open accessAbstract
KRASG12C inhibitors have revolutionized the clinical management of patients with KRASG12C-mutant lung adenocarcinoma. However, patient exposure to these inhibitors leads to the rapid onset of resistance. In this study, we have used genetically engineered mice to compare the therapeutic efficacy and the emergence of tumor resistance between genetic ablation of mutant Kras expression and pharmacological inhibition of oncogenic KRAS activity. Whereas Kras ablation induces massive tumor regression and prevents the appearance of resistant cells in vivo, treatment of KrasG12C/Trp53-driven lung adenocarcinomas with sotorasib, a selective KRASG12C inhibitor, caused a limited antitumor response similar to that observed in the clinic, including the rapid onset of resistance. Unlike in human tumors, we did not observe mutations in components of the RAS-signaling pathways. Instead, sotorasib-resistant tumors displayed amplification of the mutant Kras allele and activation of xenobiotic metabolism pathways, suggesting that reduction of the on-target activity of KRASG12C inhibitors is the main mechanism responsible for the onset of resistance. In sum, our results suggest that resistance to KRAS inhibitors could be prevented by achieving a more robust inhibition of KRAS signaling mimicking the results obtained upon Kras ablation.
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The mouse model employed two independent Cre loci to prevent the common resistance mechanism of Cre inactivation.
“This mouse model employed two independent Cre loci to prevent the common resistance mechanism of Cre inactivation.”
From KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance (2024) · cites this paper as [39]
The Results section (page not available) says the mouse model expressed two independent CreERT2 alleles and that both reduced recurrent tumors with unrecombined Kras alleles. It does not identify Cre inactivation as the mechanism, describe it as common, or say the two loci prevented it. (LLM, conf=0.86)
Experimental — accuracy not yet measuredInduced genetic deletion of mutant KRAS in the murine NSCLC tumor model Kras+/FSFG12Vlox;Trp53F/F;Rosa26-CreERT2KI/KI;Tg.hUBC-CreERT2+/T caused rapid tumor regressions.
“The induced genetic deletion of mutant KRAS in the murine NSCLC tumor model Kras+/FSFG12Vlox;Trp53F/F;Rosa26-CreERT2KI/KI;Tg.hUBC-CreERT2+/T caused rapid tumor regressions [39].”
From KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance (2024) · cites this paper as [39]
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Lung cancer: current therapies and new targeted treatments
Hirsch, F. R., Scagliotti, G. V., Mulshine, J. L., Kwon, R., Curran, W. J., Wu, Y.-L. L. C., & Paz-Ares, L. G. (2016) · The Lancet · doi:10.1016/s0140-6736(16)30958-8 · Cited by 3,278 · see citing works
K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions
Ostrem, J. M., Peters, U., Sos, M. L., Wells, J. A., & Shokat, K. M. (2013) · Nature · doi:10.1038/nature12796 · Cited by 2,557 · see citing works
The Clinical KRAS(G12C) Inhibitor AMG 510 Drives Anti-Tumour Immunity
Canon, J., Rex, K., Saiki, A. Y., Mohr, C., Cooke, K., Bagal, D., Gaida, K., Holt, T., Knutson, C. G., Koppada, N., et al. (2019) · Nature · doi:10.1038/s41586-019-1694-1 · Cited by 2,277 · see citing works
Sotorasib for Lung Cancers with <i>KRAS</i> p.G12C Mutation
Skoulidis, F., Li, B. T., Dy, G. K., Price, T. J., Falchook, G. S., Wolf, J., Italiano, A., Schuler, M., Borghaei, H., Barlesi, F., et al. (2021) · New England Journal of Medicine · doi:10.1056/nejmoa2103695 · Cited by 1,849 · see citing works
Restoration of p53 function leads to tumour regression in vivo
Ventura, A., Kirsch, D. G., McLaughlin, M. E., Tuveson, D. A., Grimm, J., Lintault, L., Newman, J., Reczek, E. E., Weissleder, R., & Jacks, T. (2007) · Nature · doi:10.1038/nature05541 · Cited by 1,820 · 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
Acquired Resistance to KRAS <sup>G12C</sup> Inhibition in Cancer
Awad, M. M., Liu, S., Rybkin, I. I., Arbour, K. C., Dilly, J., Zhu, V. W., Johnson, M. L., Heist, R. S., Patil, T., Riely, G. J., et al. (2021) · New England Journal of Medicine · doi:10.1056/nejmoa2105281 · Cited by 1,247 · see citing works
Targeting 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 · cited 1× · see citing works
“Finally, in agreement with previous observations, sotorasib inhibition was more effective in 3D spheroid cultures than in 2D monolayer cultures (31).”
Dangerous liaisons: STAT3 and NF-κB collaboration and crosstalk in cancer
Grivennikov, S. I., & Karin, M. (2010) · Cytokine & Growth Factor Reviews · doi:10.1016/j.cytogfr.2009.11.005 · Cited by 1,160 · see citing works
The Frequency of Ras Mutations in Cancer
Prior, I. A., Hood, F. E., & Hartley, J. L. (2020) · Cancer Research · doi:10.1158/0008-5472.can-19-3682 · Cited by 1,130 · see citing works
Understanding and targeting resistance mechanisms in NSCLC
Rotow, J. K., & Bivona, T. G. (2017) · Nature reviews. Cancer · doi:10.1038/nrc.2017.84 · Cited by 978 · see citing works
Ruzankina, Y., Pinzon‐Guzman, C., Asare, A., Ong, T., Pontano, L. L., Cotsarelis, G., Zediak, V. P., Velez, M., Bhandoola, A., & Brown, E. J. (2007) · Cell stem cell · doi:10.1016/j.stem.2007.03.002 · Cited by 780 · see citing works
Selective inhibition of oncogenic KRAS output with small molecules targeting the inactive state
Patricelli, M. P., Janes, M. R., Li, L.-S., Hansen, R., Peters, U., Kessler, L. V., Chen, Y., Kucharski, J. M., Feng, J., Ely, T., et al. (2016) · Cancer Discovery · doi:10.1158/2159-8290.cd-15-1105 · Cited by 759 · see citing works
Allele-specific inhibitors inactivate mutant KRAS G12C by a trapping mechanism
Lito, P., Solomon, M., Li, L.-S., Hansen, R., & Rosen, N. (2016) · Science · doi:10.1126/science.aad6204 · Cited by 691 · see citing works
Gritsko, T., Williams, A., Turkson, J., Kaneko, S., Bowman, T., Huang, M., Nam, S., Eweis, I., Diaz, N., Sullivan, D., et al. (2006) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-04-1752 · Cited by 563 · see citing works
The Differential Effects of Mutant <i>p53</i> Alleles on Advanced Murine Lung Cancer
Jackson, E. L., Olive, K. P., Tuveson, D. A., Bronson, R., Crowley, D., Brown, M., & Jacks, T. (2005) · Cancer Research · doi:10.1158/0008-5472.can-05-2193 · Cited by 553 · see citing works
Rapid non-uniform adaptation to conformation-specific KRAS(G12C) inhibition
Xue, J. Y., Zhao, Y., Aronowitz, J., Mai, T. T., Vides, A., Qeriqi, B., Kim, D., Li, C., de Stanchina, E., Mazutis, L., et al. (2020) · Nature · doi:10.1038/s41586-019-1884-x · Cited by 543 · see citing works
Anti-tumor efficacy of a potent and selective non-covalent KRASG12D inhibitor
Hallin, J., Bowcut, V., Calinisan, A., Briere, D. M., Hargis, L., Engstrom, L. D., Laguer, J., Medwid, J., Vanderpool, D., Lifset, E., et al. (2022) · Nature Medicine · doi:10.1038/s41591-022-02007-7 · Cited by 533 · see citing works
Tanaka, N., Lin, J. J., Li, C., Ryan, M. B., Zhang, J., Kiedrowski, L. A., Michel, A. G., Syed, M. U., Fella, K. A., Sakhi, M., et al. (2021) · Cancer Discovery · doi:10.1158/2159-8290.cd-21-0365 · Cited by 527 · see citing works
Vertical Pathway Inhibition Overcomes Adaptive Feedback Resistance to KRASG12C Inhibition
Ryan, M. B., Fece de la Cruz, F., Phat, S., Myers, D. T., Wong, E., Shahzade, H. A., Hong, C. B., & Corcoran, R. B. (2020) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-19-3523 · Cited by 496 · cited 1× · see citing works
“Other mechanisms of adaptive resistance to KRAS G12C inhibition, including feedback upregulation of a variety of RTKs or AURKA, have been described (14, 49–51).”
Diverse alterations associated with resistance to KRAS(G12C) inhibition
Zhao, Y., Murciano-Goroff, Y. R., Xue, J. Y., Ang, A., Lucas, J., Mai, T. T., Da Cruz Paula, A. F., Saiki, A. Y., Mohn, D., Achanta, P., et al. (2021) · Nature · doi:10.1038/s41586-021-04065-2 · Cited by 479 · see citing works
FAS and NF-κB signalling modulate dependence of lung cancers on mutant EGFR
Bivona, T. G., Hieronymus, H., Parker, J., Chang, K., Taron, M., Rosell, R., Moonsamy, P., Dahlman, K., Miller, V. A., Costa, C., et al. (2011) · Nature · doi:10.1038/nature09870 · Cited by 396 · see citing works
Efficacy of a small-molecule inhibitor of KrasG12D in immunocompetent models of pancreatic cancer
Kemp, S. B., Cheng, N., Markosyan, N., Sor, R., Kim, I.-K., Hallin, J., Shoush, J., Quinones, L., Brown, N. V., Bassett, J. B., et al. (2023) · Cancer Discovery · doi:10.1158/2159-8290.cd-22-1066 · Cited by 370 · see citing works
The mutational landscapes of genetic and chemical models of Kras-driven lung cancer
Westcott, P. M. K., Halliwill, K. D., To, M. D., Rashid, M., Rust, A. G., Keane, T., Delrosario, R., Jen, K., Gurley, K. E., Kemp, C. J., et al. (2014) · Nature · doi:10.1038/nature13898 · Cited by 333 · see citing works
Blasco, R. B., Francoz, S., Santamaría, D., Cañamero, M., Dubus, P., Charron, J., Baccarini, M., & Barbacid, M. (2011) · Cancer Cell · doi:10.1016/j.ccr.2011.04.002 · Cited by 302 · see citing works
Koga, T., Suda, K., Fujino, T., Ohara, S., Hamada, A., Nishino, M., Chiba, M., Shimoji, M., Takemoto, T., Arita, T., et al. (2021) · Journal of Thoracic Oncology · doi:10.1016/j.jtho.2021.04.015 · Cited by 265 · see citing works
Amplification of EGFR T790M causes resistance to an irreversible EGFR inhibitor
Ercan, D., Zejnullahu, K., Yonesaka, K., Xiao, Y., Capelletti, M., Rogers, A. M., Lifshits, E., Brown, A., Lee, C., Christensen, J. G., et al. (2010) · Oncogene · doi:10.1038/onc.2009.526 · Cited by 229 · see citing works
Little, A. S., Balmanno, K., Sale, M. J., Newman, S., Dry, J. R., Hampson, M., Edwards, P. A., Smith, P. D., & Cook, S. J. (2011) · Science Signaling · doi:10.1126/scisignal.2001752 · Cited by 211 · see citing works
Blakely, C. M., Pazarentzos, E., Olivas, V., Asthana, S., Yan, J. J., Tan, I., Hrustanovic, G., Chan, E., Lin, L., Neel, D. S., et al. (2015) · Cell Reports · doi:10.1016/j.celrep.2015.03.012 · Cited by 204 · see citing works
McFadden, D. G., Politi, K., Bhutkar, A., Chen, F. K., Song, X., Pirun, M., Santiago, P. M., Kim-Kiselak, C., Platt, J. T., Lee, E., et al. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1613601113 · Cited by 194 · see citing works
An approach to suppress the evolution of resistance in BRAFV600E-mutant cancer
Xue, Y., Martelotto, L., Baslan, T., Vides, A., Solomon, M., Mai, T. T., Chaudhary, N., Riely, G. J., Li, B. T., Scott, K., et al. (2017) · Nature Medicine · doi:10.1038/nm.4369 · Cited by 174 · see citing works
Briere, D. M., Li, S., Calinisan, A., Sudhakar, N., Aranda, R., Hargis, L., Peng, D. H., Deng, J., Engstrom, L. D., Hallin, J., et al. (2021) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-20-0462 · Cited by 168 · see citing works
Mechanisms of Resistance to KRASG12C-Targeted Therapy
Akhave, N. S., Biter, A. B., & Hong, D. S. (2021) · Cancer Discovery · doi:10.1158/2159-8290.cd-20-1616 · Cited by 156 · see citing works
Weiss, A., Lorthiois, E., Barys, L., Beyer, K. S., Bomio-Confaglia, C., Burks, H., Chen, X., Cui, X., de Kanter, R., Dharmarajan, L., et al. (2022) · Cancer Discovery · doi:10.1158/2159-8290.cd-22-0158 · Cited by 150 · see citing works
Molecular Characterization of Acquired Resistance to KRASG12C–EGFR Inhibition in Colorectal Cancer
Yaeger, R., Mezzadra, R., Sinopoli, J., Bian, Y., Marasco, M., Kaplun, E., Gao, Y., Zhao, H., Paula, A. D. C., Zhu, Y., et al. (2023) · Cancer Discovery · doi:10.1158/2159-8290.cd-22-0405 · Cited by 144 · see citing works
Sanclemente, M., Francoz, S., Esteban-Burgos, L., Bousquet-Mur, E., Djurec, M., Lopez-Casas, P. P., Hidalgo, M., Guerra, C., Drosten, M., Musteanu, M., et al. (2018) · Cancer Cell · doi:10.1016/j.ccell.2017.12.014 · Cited by 119 · see citing works
Self-citationKRAS is vulnerable to reversible switch-II pocket engagement in cells
Vasta, J. D., Peacock, D. M., Zheng, Q., Walker, J. A., Zhang, Z., Zimprich, C. A., Thomas, M. R., Beck, M. T., Binkowski, B. F., Corona, C. R., et al. (2022) · Nature Chemical Biology · doi:10.1038/s41589-022-00985-w · Cited by 115 · see citing works
Targeting survivin overcomes drug resistance in acute lymphoblastic leukemia
Park, E., Gang, E. J., Hsieh, Y., Schaefer, P., Chae, S., Klemm, L., Huantes, S., Loh, M. L., Conway, E. M., Kang, E., et al. (2011) · Blood · doi:10.1182/blood-2011-04-351239 · Cited by 108 · see citing works
Cell Type–Specific Adaptive Signaling Responses to KRASG12C Inhibition
Solanki, H. S., Welsh, E. A., Fang, B., Izumi, V., Darville, L., Stone, B., Franzese, R., Chavan, S., Kinose, F., Imbody, D., et al. (2021) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-20-3872 · Cited by 106 · see citing works
Rapid idiosyncratic mechanisms of clinical resistance to KRAS G12C inhibition
Tsai, Y. S., Woodcock, M. G., Azam, S. H., Thorne, L. B., Kanchi, K. L., Parker, J. S., Vincent, B. G., & Pecot, C. V. (2022) · Journal of Clinical Investigation · doi:10.1172/jci155523 · Cited by 103 · see citing works
Direct Targeting KRAS Mutation in Non-Small Cell Lung Cancer: Focus on Resistance
Reita, D., Pabst, L., Pencreach, E., Guérin, É., Dano, L., Rimelen, V., Voegeli, A., Vallat, L. D., Mascaux, C., & Beau‐Faller, M. (2022) · Cancers · doi:10.3390/cancers14051321 · Cited by 101 · see citing works
Cui, X., Shen, D., Kong, C., Zhang, Z., Zeng, Y., Lin, X., & Liu, X. (2017) · Scientific Reports · doi:10.1038/srep40723 · Cited by 97 · see citing works
Rapid idiosyncratic mechanisms of clinical resistance to KRAS G12C inhibition
Tsai, Y., Woodcock, M. G., Azam, S. H., Thorne, L. B., Kanchi, K., Parker, J. S., Vincent, B. G., & Pecot, C. V. (2022) · DOAJ (DOAJ: Directory of Open Access Journals) · Cited by 87 · see citing works
Drugging the Undruggable: Advances on RAS Targeting in Cancer
Molina‐Arcas, M., Samani, A., & Downward, J. (2021) · Genes · doi:10.3390/genes12060899 · Cited by 73 · see citing works
A FRT-flankedp53mouse to generate primary tumors with Flp recombinase
Lee, C., Moding, E. J., Huang, X., Li, Y., Woodlief, L. Z., Rodrigues, R. C., Ma, Y., & Kirsch, D. G. (2011) · Disease Models & Mechanisms · doi:10.1242/dmm.009084 · Cited by 69 · see citing works
Kras mutant genetically engineered mouse models of human cancers are genomically heterogeneous
Chung, W., Daemen, A., Cheng, J. H., Long, J. E., Cooper, J. E., Wang, B.-E., Tran, C., Singh, M., Gnad, F., Modrusan, Z. D., et al. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1708391114 · Cited by 61 · see citing works
Targeting KRAS Mutant in Non-Small Cell Lung Cancer: Novel Insights Into Therapeutic Strategies
Désage, A.-L., Léonce, C., Swalduz, A., & Ortiz‐Cuaran, S. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.796832 · Cited by 60 · see citing works
Sale, M. J., Balmanno, K., Saxena, J., Ozono, E., Wojdyła, K., McIntyre, R. E., Gilley, R., Woroniuk, A., Howarth, K., Hughes, G. D., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-09438-w · Cited by 52 · see citing works
Lechler, P., Renkawitz, T. F., Câmpean, V., Balakrishnan, S., Tingart, M., Grifka, J. K., & Schaumburger, J. (2011) · BMC Cancer · doi:10.1186/1471-2407-11-120 · Cited by 51 · see citing works
Targeting KRAS mutant lung cancer: light at the end of the tunnel
Drosten, M., & Barbacid, M. (2021) · Molecular Oncology · doi:10.1002/1878-0261.13168 · Cited by 47 · see citing works
Self-citationKSR induces RAS‐independent MAPK pathway activation and modulates the efficacy of KRAS inhibitors
Paniagua, G., Jacob, H. K. C., Brehey, O., García‐Alonso, S., Lechuga, C. G., Pons, T., Musteanu, M., Guerra, C., Drosten, M., & Barbacid, M. (2022) · Molecular Oncology · doi:10.1002/1878-0261.13213 · Cited by 34 · see citing works
Self-citationEscaping KRAS: Gaining Autonomy and Resistance to KRAS Inhibition in KRAS Mutant Cancers
Adachi, Y., Kimura, R., Hirade, K., & Ebi, H. (2021) · Cancers · doi:10.3390/cancers13205081 · Cited by 28 · see citing works
Dwyer‐Nield, L. D., McQuillan, J. J., Hill‐Baskin, A. E., Radcliffe, R. A., You, M., Nadeau, J. H., & Malkinson, A. M. (2009) · International Journal of Cancer · doi:10.1002/ijc.24743 · Cited by 27 · see citing works
The promise and peril of KRAS G12C inhibitors
Moore, A. R., & Malek, S. (2021) · Cancer Cell · doi:10.1016/j.ccell.2021.07.011 · Cited by 22 · see citing works
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 · see citing works
Manabe, T., & Bivona, T. G. (2022) · Journal of Clinical Investigation · doi:10.1172/jci156891 · Cited by 17 · see citing works
Loos, N. H. C., Retmana, I. A., Li, W., Martins, M. L. F., Lebre, M. C., Sparidans, R. W., Beijnen, J. H., & Schinkel, A. H. (2022) · Pharmacological Research · doi:10.1016/j.phrs.2022.106137 · Cited by 14 · see citing works
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- [54]Lee CL et al Generation of primary tumors with Flp recombinase in FRT-flanked p53 mice Dis Model Mech 2012 5 3 397 402 22228755 PMC3339833
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Sorted by citations
Adeno-to-squamous transition drives resistance to KRAS inhibition in LKB1 mutant lung cancer
Tong, X., Patel, A. S., Kim, E., Li, H., Chen, Y., Li, S., Liu, S., Dilly, J., Kapner, K. S., Zhang, N., et al. (2024) · Cancer Cell · doi:10.1016/j.ccell.2024.01.012 · Cited by 142 · see citing works
Modulation of the proteostasis network promotes tumor resistance to oncogenic KRAS inhibitors
Lv, X., Lu, X., Cao, J., Luo, Q., Ding, Y., Peng, F., Pataer, A., Lu, D., Han, D., Malmberg, E., et al. (2023) · Science · doi:10.1126/science.abn4180 · Cited by 123 · see citing works
López-Estévez, A. M., Lapuhs, P., Pineiro‐Alonso, L., & Alonso, M. J. (2023) · Advanced Materials · doi:10.1002/adma.202309355 · Cited by 90 · see citing works
Alveolar Differentiation Drives Resistance to <i>KRAS</i> Inhibition in Lung Adenocarcinoma
Li, Z., Zhuang, X., Pan, C.-H., Yan, Y., Thummalapalli, R., Hallin, J., Torborg, S., Singhal, A., Chang, J. C., Manchado, E., et al. (2024) · Cancer Discovery · doi:10.1158/2159-8290.cd-23-0289 · Cited by 74 · see citing works
RAS-ON inhibition overcomes clinical resistance to KRAS G12C-OFF covalent blockade
Nokin, M., Mira, A., Patrucco, E., Ricciuti, B., Cousin, S., Soubeyran, I., José, S. S., Peirone, S., Caizzi, L., Michelina, S. V., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-51828-2 · Cited by 68 · see citing works
Response and Resistance to RAS Inhibition in Cancer
Ebright, R. Y., Dilly, J., Shaw, A. T., & Aguirre, A. J. (2025) · Cancer Discovery · doi:10.1158/2159-8290.cd-25-0349 · Cited by 70 · see citing works
KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance
Ash, L. J., Busia-Bourdain, O., Okpattah, D., Kamel, A., Liberchuk, A., & Wolfe, A. L. (2024) · Current Oncology · doi:10.3390/curroncol31040150 · Cited by 59 · see citing works
“Early iterations of this compound were selective for the GDP-bound state, effectively locking KRAS G12C in its inactive form (Figure 3) [47].”
BackgroundKRAS G12C-mutant driven non-small cell lung cancer (NSCLC)
Rosell, R., Codony‐Servat, J., González, J., Santarpía, M., Jain, A. S., Shivamallu, C., Wang, Y., Giménez-Capitán, A. A., Molina‐Vila, M. Á., Nilsson, J. A., et al. (2023) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2023.104228 · Cited by 39 · see citing works
A first-in-class EGFR-directed KRAS G12V selective inhibitor
Stanland, L. J., Huggins, H. P., Sahoo, S. S., Porrello, A., Chareddy, Y. S., Azam, S. H., Perry, J. L., Pallan, P. S., Whately, K. M., Edatt, L., et al. (2025) · Cancer Cell · doi:10.1016/j.ccell.2025.05.016 · Cited by 31 · see citing works
Macaya, I., Román, M., Welch, C., Entrialgo‐Cadierno, R., Salmón, M., Santos, A., Feliu, I., Kovalski, J. R., López, I., Rodríguez‐Remírez, M., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-41828-z · Cited by 21 · see citing works
Self-citationKhan, H. Y., Nagasaka, M., Aboukameel, A., Alkhalili, O. A., Uddin, M. H., Bannoura, S. F., Mzannar, Y., Azar, I. H., Beal, E. W., Tobon, M. E., et al. (2023) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-23-0251 · Cited by 18 · see citing works
Targeted degradation of oncogenic KRASG12V triggers antitumor immunity in lung cancer models
Li, D., Geng, K., Yuan, H., Gu, J., Kumar, S., Olson, A. T., Kuismi, C. C., Kim, H. M., Pan, Y., Sherman, F., et al. (2024) · Journal of Clinical Investigation · doi:10.1172/jci174249 · Cited by 17 · see citing works
Facts and Hopes in Immunotherapy Strategies Targeting Antigens Derived from KRAS Mutations
Linette, G. P., Bear, A. S., & Carreno, B. M. (2024) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-23-1212 · Cited by 14 · see citing works
Parry, C., Pellicano, F., Schüttelkopf, A. W., Beyer, K. S., Bower, J. F., Bryson, A., Cameron, K., Cerutti, N. M., Clark, J. P., Davidson, S. C., et al. (2025) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.4c02929 · Cited by 12 · see citing works
Nolan, A. A., Raso, C., Kölch, W., von Kriegsheim, A., Wynne, K. J., & Matallanas, D. (2023) · Cancers · doi:10.3390/cancers15164141 · Cited by 12 · see citing works
Solanki, H. S., Shah, H., Imbody, D. J., Desai, B., Kato, R., Miroshnychenko, D., Stern, Y. E., Majumder, A., Sarcar, B., Xieraili, A., et al. (2025) · Cancer Research · doi:10.1158/0008-5472.can-25-0600 · Cited by 10 · see citing works
López-Estévez, A. M., Sanjurjo, L., Turrero, Á., Arriaga, I., Abrescia, N. G. A., Poveda, A. M., Jiménez‐Barbero, J., Vidal, A., Torres, D., & Alonso, M. J. (2024) · Journal of Controlled Release · doi:10.1016/j.jconrel.2024.07.032 · Cited by 9 · see citing works
Mesenchymal Stem Cell-Derived Exosomes in Cancer Resistance Against Therapeutics
Vignesh Balaji, E., Pai, K. M., & Pai, K. S. R. (2025) · Cancers · doi:10.3390/cancers17050831 · Cited by 7 · see citing works
Blocking C-terminal processing of KRAS4b via a direct covalent attack on the CaaX-box cysteine
Maciag, A. E., Yang, Y., Sharma, A. K., Turner, D. M., DeHart, C. J., Abdelkarim, H., Fan, L., Smith, B. P., Kumari, V., Dyba, M. D., et al. (2025) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2410766122 · Cited by 7 · see citing works
Synthetic approaches and clinical application of KRAS inhibitors for cancer therapy
Jiang, M., Ma, S., Xuan, Y., & Chen, K. (2025) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2025.117626 · Cited by 6 · see citing works
Oncogenic dependency plays a dominant role in the immune response to cancer
Li, J., D’Amico, S., Kirillov, V., Petrenko, O., & Reich, N. C. (2023) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2308635120 · Cited by 6 · see citing works
Cornilescu, G., Bindu, L. K., Sternicki, L. M., Chao, F.-A., Gillette, W., Fer, N. D., Colombus, J., Castillo, J., Bonilla, P. A., Van, Q. N., et al. (2024) · ACS Pharmacology & Translational Science · doi:10.1021/acsptsci.4c00075 · Cited by 5 · see citing works
Targeting KRAS-G12C in lung cancer: The emerging role of PROTACs in overcoming resistance
Chidambaram, K., Rekha, A., Goyal, A., & Rana, M. (2025) · Pathology - Research and Practice · doi:10.1016/j.prp.2025.155954 · Cited by 5 · see citing works
Anticancer activity of RAS-GTP inhibition in cholangiocarcinoma
Entrialgo‐Cadierno, R., Morali, K., Feliu, I., Wang, Y., Evans, J., Yáñez-Bartolomé, M., López, I., Macaya, I., Cueto‐Ureña, C., Sin-Coscujuela, D., et al. (2026) · Cancer Cell · doi:10.1016/j.ccell.2026.03.020 · Cited by 4 · see citing works
Bağcı, Ö. (2024) · Biology of the Cell · doi:10.1111/boc.202400017 · Cited by 3 · see citing works
Intratumor heterogeneity in KRAS signaling shapes treatment resistance
Petrenko, O., Kirillov, V., D’Amico, S., & Reich, N. C. (2024) · iScience · doi:10.1016/j.isci.2024.111662 · Cited by 3 · see citing works
Hamilton, G., Stickler, S., & Rath, B. (2023) · Exploration of Targeted Anti-tumor Therapy · doi:10.37349/etat.2023.00178 · Cited by 3 · see citing works
Ivanišević, T., Magits, W., Ma, Y., Zhao, P., Boxel, E. V., Lechat, B., Stites, E. C., Velde, G. V., Sewduth, R. N., & Sablina, A. A. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.02.27.582346 · Cited by 3 · see citing works
Cai, L., Wu, F., Zhou, Q., Gao, Y., Yao, B., DeBerardinis, R. J., Acquaah-Mensah, G. K., Aidinis, V., Beane, J., Biswal, S., et al. (2025) · Cancer Research · doi:10.1158/0008-5472.can-24-1607 · Cited by 2 · see citing works
Rosell, R., Pedraz‐Valdunciel, C., Jain, A. S., Shivamallu, C., & Aguilar, A. (2024) · Expert Opinion on Investigational Drugs · doi:10.1080/13543784.2024.2320710 · Cited by 2 · see citing works
STAT3 sustains tumorigenicity following mutant KRAS ablation
D’Amico, S., Kirillov, V., Liu, J., Qiu, Z., Lei, X., Qin, H., Sheridan, B. S., & Reich, N. C. (2025) · EMBO Reports · doi:10.1038/s44319-025-00563-w · Cited by 2 · see citing works
Association of KRAS Gene and microRNA-124-3p in Sporadic Colorectal Tumours
Bağcı, Ö. (2024) · Journal of Biosciences and Medicines · doi:10.4236/jbm.2024.121013 · Cited by 1 · see citing works
Jean-Francois, F. L. (2024) · Elsevier eBooks · doi:10.1016/b978-0-443-21861-3.00010-3 · Cited by 1 · see citing works
Dual Inhibitors of KRASG12D and HSP90 Are Effective against KRASG12D Inhibitor Resistance
Pulido, I., Gunder, L. C., Ying, C., Wang, Y., Dai, Y., Yang, Z., Rahnama, A., Li, J., Sun, Y., Liu, C., et al. (2025) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-24-1173 · Cited by 1 · see citing works
The repressor Capicua is a barrier to lung tumor development driven by Kras/Trp53 mutations
Ballesteros-González, I., Hernández-Navas, I., Brehey, O., Lechuga, C. G., Salmón, M., Scotece, M., Velasco-Vicente, R., Flores-Gómez, A. A., Cebriá, A., Simón-Carrasco, L., et al. (2025) · EMBO Molecular Medicine · doi:10.1038/s44321-025-00326-z · Cited by 1 · see citing works
Self-citationIntrinsic resistance to RAS inhibitors is driven by dysregulation of KRAS degradation
Ivanišević, T., Ma, Y., Boxel, E. V., Magits, W., Lechat, B., Koçberber, Z., Willnow, P., Fendt, S., Velde, G. V., Sewduth, R. N., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-67109-5 · Cited by 2 · see citing works
Cuesta-López, L., de la Rosa, I. A., Pérez‐Sánchez, C., Betancourt, A. B., Ruiz-Ponce, M., Barranco, A. M., Ortiz-Buitrago, P., Ladehesa-Pineda, L., Puche-Larrubia, M. Á., Martin-Salazar, E., et al. (2026) · RMD Open · doi:10.1136/rmdopen-2025-006136 · Cited by 1 · see citing works
Lineage identity governs oncogene dependence in mouse NSCLC models of KRAS inhibitor resistance
Mathey‐Andrews, N., Rodriguez, C. L., Shui, B., Patriotis, A. L., Rideout, W. M., Chen, V. Z., Murazzi, I., Ghazi, P., Cornwall-Brady, M. R., Liu, M., et al. (2026) · Nature Genetics · doi:10.1038/s41588-026-02768-8 · Cited by 1 · see citing works
KRAS combination strategies: How well aligned is clinical and preclinical research?
Nadal, E., Ambrogio, C., Santamarı́a, D., & Lindsay, C. R. (2024) · Elsevier eBooks · doi:10.1016/b978-0-443-21861-3.00018-8 · Cited by 1 · see citing works
Adeno-to-squamous transition drives resistance to KRAS inhibition in LKB1 mutant lung cancerPreprint
Tong, X., Patel, A. S., Kim, E., Li, H., Chen, Y., Li, S., Liu, S., Dilly, J., Kapner, K. S., Xue, Y., et al. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.09.07.556567 · Cited by 1 · see citing works
Kourtis, S., Cianferoni, D., Serrano, L., & Sdelci, S. (2024) · Scientific Data · doi:10.1038/s41597-024-03394-x · Cited by 1 · see citing works
Targeted KRAS G12V degradation elicits efficient and durable lung adenocarcinoma regression in vivoPreprint
Martín, A. J. M., García-Pérez, I. M., José, S. S., Rojo, P., Riego‐Mejías, C., Teodósio, C., Barbosa, B. M. G., Sánchez, C., Folch-I-Casanovas, I., Caballol, A. O., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.12.13.627539 · Cited by 1 · see citing works
miRNA Profiling of 3'UTR Variations in Sporadic Lung Carcinoma TumoursPreprint
Bağcı, Ö. (2023) · Research Square · doi:10.21203/rs.3.rs-3638249/v1
Peptidoform analysis of IP-MS data allows detection of differentially present bait proteoformsPreprint
Kourtis, S., Cianferoni, D., Serrano, L. G., & Sdelci, S. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.01.23.576810
Yi, Y., Hu, Y., Ren, S., Wu, Y., Chen, X.-S., Lu, Y., Yu, Q., Zuo, D., Bi, G., Wang, Q., et al. (2026) · Respiratory Research · doi:10.1186/s12931-026-03673-8
SAIMSARA (2026) · SAIMSARA Journal · doi:10.62487/saimsaradc4d1e0f
KRASG12V Degraders Provide a Potential Therapeutic Opportunity in Lung Adenocarcinoma
Borrego, S. G., & Misale, S. (2026) · Cancer Research · doi:10.1158/0008-5472.can-26-2186
Wang, C., Ghosh, P., Jin, S., Bai, L., Aguilar, A., McEachern, D., Wang, M., Li, Q., Wen, B., Sun, D., et al. (2026) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.6c01153
Coma, S., Musteanu, M., Malvezzi, C. C., Jamieson, R., Patrucco, E., Mira, A., Dilly, J., Li, Z., Fernández‐Rodríguez, A., López-García, A., et al. (2026) · Science Translational Medicine · doi:10.1126/scitranslmed.aea4608
Self-citationPadhye, A., Kang, K., Kong, F. Y., Sindoni, N., Yu, Q., 姜, 柏., Chang, W.-H., Coker, O., Kim, E., Dilly, J., et al. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.10.01.756013
BindingDB (2026) · UC San Diego · doi:10.7270/q27p94b7
- Authors
- Salmón, M., Álvarez-Díaz, R., Fustero-Torre, C., Brehey, O., Lechuga, C. G., Sanclemente, M., Fernández-García, F., López-García, A., Martín-Guijarro, M. C., Rodríguez-Perales, S., Bousquet-Mur, E., Morales-Cacho, L., Mulero, F., Al-Shahrour, F., Martínez, L., Domínguez, O., Caleiras, E., Ortega, S., Guerra, C., Musteanu, M., Drosten, M., & Barbacid, M.
- Affiliations
- Spanish National Cancer Research Centre (ES)
- Instituto de Salud Carlos III (ES)
- Consejo Superior de Investigaciones Científicas (ES)
- Corresponding author
- Drosten, Matthias
- Barbacid, Mariano
- ORCID
- Salmón, Marina
- Álvarez-Díaz, Ruth
- Fustero-Torre, Coral
- Lechuga, Carmen G.
- Sanclemente, Manuel
- Fernández-García, Fernando
- López-García, Alejandra
- Rodríguez-Perales, Sandra
- Mulero, Francisca
- Al-Shahrour, Fátima
- Domínguez, Orlando
- Caleiras, Eduardo
- Ortega, Sagrario
- Guerra, Carmen
- Musteanu, Monica
- Drosten, Matthias
- Barbacid, Mariano
- Venue
- Journal of Clinical Investigation
- Published
- 2023-04-03
- Volume
- 133
- Issue
- 7
- ISSN
- 0021-9738 (ISSN-L)
- 1558-8238
- PMC
- PMC10065067
- OpenAlex
- W4327626369
- Cited by
- 52
- References
- 57
- Citations by year
- 2026: 11 · 2025: 13 · 2024: 17 · 2023: 11
- FWCI
- 9.58
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Journal of Clinical Investigation (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- H2020 European Research Council (ERC-AG/695566,THERACAN)
- Ministerio de Ciencia e Innovación (RTI2018-094664-B-I00, RTC2017-6576-1, PID2020-116705RB-100)
- Comunidad de Madrid (B2017/BMD-3884 iLUNG-CM)
- CRIS Cancer Foundation (MB grant)
- Fundación Científica Asociación Española Contra el Cáncer (GC166173694BARB, LABAE20049RODR, LABAE211678DROS)
- Instituto de Salud Carlos III (PI20/01837, PI19/00514)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Keywords
- KRAS G12C, lung adenocarcinoma, sotorasib, KRAS inhibitor resistance, gene ablation, xenobiotic metabolism, KRAS amplification, Ras signaling, Trp53, genetically engineered mouse models, antitumor efficacy
- MeSH terms
- Adenocarcinoma of Lung, Animals, Lung Neoplasms, Mutation, Oncogenes, Signal Transduction, Proto-Oncogene Proteins p21(ras), Mice
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