Glecirasib, a Potent and Selective Covalent KRAS G12C Inhibitor Exhibiting Synergism with Cetuximab or SHP2 Inhibitor JAB-3312
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Abstract
Clinical studies have demonstrated the antitumor efficacy of covalent KRAS G12C inhibitors in treating advanced/metastatic cancers. In the current study, we report the preclinical characteristics of a specific KRAS p.G12C covalent inhibitor, glecirasib. Glecirasib exhibited high potency against KRAS G12C, along with a high level of selectivity over wild-type KRAS, HRAS, and NRAS in biochemical assays. On the cellular level, it substantially reduced downstream ERK and AKT phosphorylation, inhibited the viability of cancer cells harboring the KRAS p.G12C mutation, and demonstrated high selectivity over non-KRAS p.G12C cancer cells. Glecirasib could effectively inhibit HRAS G12C, NRAS G12C, and several G12C-inclusive KRAS double mutants that showed resistance to adagrasib. In vivo research suggested that once-daily dosing of glecirasib can robustly inhibit ERK phosphorylation for at least 24 hours and induced tumor regression in several xenograft models, including the NCI-H1373–luciferase intracranial model. Glecirasib in combination with cetuximab or JAB-3312 (sitneprotafib, a clinical-stage SHP2 inhibitor developed by Jacobio Pharma) significantly enhanced antitumor activity both in vitro and in vivo. Collectively, these results suggest that glecirasib is a potent and selective covalent inhibitor of KRAS G12C, shows potent antitumor activity as monotherapy, and synergizes with either EGFR blockade or SHP2 inhibition. A new drug application for glecirasib has been submitted in China, seeking approval for the treatment of non–small cell lung cancer, supported by a pivotal phase II single-arm study (NCT05009329). Additionally, glecirasib is being explored in clinical trials in combination with cetuximab (phase II, NCT05194995) and JAB-3312 (phase III, NCT06416410). Significance: Glecirasib potently and selectively inhibits KRAS G12C and reduces ERK and AKT phosphorylation in KRAS G12C–mutant cancer cells, further inducing cell-cycle arrest and apoptosis. Glecirasib monotherapy leads to tumor regression in KRAS G12C–mutant animal models and shows synergistic effects with cetuximab or JAB-3312 (sitneprotafib).
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Cites
Bray, F., Laversanne, M., Sung, H., Ferlay, J., Siegel, R. L., Soerjomataram, I., & Jemal, A. (2024) · CA: a cancer journal for clinicians · doi:10.3322/caac.21834 · Cited by 27,064 · see citing works
Chou, T.-C., & Talalay, P. (1984) · Advances in Enzyme Regulation · doi:10.1016/0065-2571(84)90007-4 · Cited by 7,178 · see citing works
Global quantification of mammalian gene expression control
Schwanhäusser, B., Busse, D., Li, N., Dittmar, G., Schuchhardt, J., Wolf, J., Chen, W., & Selbach, M. (2011) · Nature · doi:10.1038/nature10098 · Cited by 6,566 · see citing works
Thai, A. A., Solomon, B., Sequist, L. V. D., Gainor, J. F., & Heist, R. S. (2021) · The Lancet · doi:10.1016/s0140-6736(21)00312-3 · Cited by 2,629 · 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
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
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
Adagrasib in Non–Small-Cell Lung Cancer Harboring a <i> KRAS <sup>G12C</sup> </i> Mutation
Jänne, P. A., Riely, G. J., Gadgeel, S. M., Heist, R. S., Ou, S.-H. I., Pacheco, J. M., Johnson, M. L., Sabari, J. K., Leventakos, K., Yau, E., et al. (2022) · New England Journal of Medicine · doi:10.1056/nejmoa2204619 · Cited by 1,061 · see citing works
Copeland, R. A. (2005) · PubMed · Cited by 1,045 · see citing works
Zheng, S., Wang, W., Aldahdooh, J., Malyutina, A., Shadbahr, T., Tanoli, Z., Pessia, A., & Tang, J. (2022) · Genomics, Proteomics & Bioinformatics · doi:10.1016/j.gpb.2022.01.004 · Cited by 733 · 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
Fell, J. B., Fischer, J. P., Baer, B. R., Blake, J. F., Bouhana, K., Briere, D. M., Brown, K. D., Burgess, L. E., Burns, A. C., Burkard, M. R., et al. (2020) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.9b02052 · Cited by 653 · cited 1× · see citing works
“Cocrystal structures have revealed that adagrasib formed a vital hydrogen bond with the His95 of KRAS G12C (34), a bond not observed with gle-cirasib (18), sotorasib (33), or JDQ443 (35).”
de Langen, A. J., Johnson, M. L., Mazieres, J., Dingemans, A.-M. C., Mountzios, G., Pless, M., Wolf, J., Schuler, M., Lena, H., Skoulidis, F., et al. (2023) · The Lancet · doi:10.1016/s0140-6736(23)00221-0 · Cited by 619 · see citing works
Self-citationMaurer, T., Garrenton, L. S., Oh, A., Pitts, K., Anderson, D. J., Skelton, N. J., Fauber, B. P., Pan, B., Malek, S., Stokoe, D., et al. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1116510109 · Cited by 618 · see citing works
EGFR Blockade Reverts Resistance to KRASG12C Inhibition in Colorectal Cancer.
Amodio, V., Yaeger, R., Arcella, P., Cancelliere, C., Lamba, S., Lorenzato, A., Arena, S., Montone, M., Mussolin, B., Bian, Y., et al. (2020) · Cancer Discovery · doi:10.1158/2159-8290.cd-20-0187 · Cited by 504 · see citing works
Singhal, A., Li, B. T., & O'Reilly, E. M. (2024) · Nature Medicine · doi:10.1038/s41591-024-02903-0 · Cited by 358 · see citing works
Single-Agent Divarasib (GDC-6036) in Solid Tumors with a <i>KRAS</i> G12C Mutation
Sacher, A., LoRusso, P., Patel, M. R., Miller, W. H., Garralda, E., Forster, M. D., Santoro, A., Falcon, A., Kim, T. W., Paz-Ares, L., et al. (2023) · New England Journal of Medicine · doi:10.1056/nejmoa2303810 · Cited by 328 · see citing works
Clinical Implications of Genomic Discoveries in Lung Cancer
Swanton, C., & Govindan, R. (2016) · New England Journal of Medicine · doi:10.1056/nejmra1504688 · Cited by 271 · see citing works
Chemical remodeling of a cellular chaperone to target the active state of mutant KRAS
Schulze, C. J., Seamon, K. J., Zhao, Y., Yang, Y. C., Cregg, J., Kim, D., Tomlinson, A., Choy, T. J., Wang, Z., Sang, B., et al. (2023) · Science · doi:10.1126/science.adg9652 · Cited by 264 · 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
Yaeger, R., Uboha, N. V., Pelster, M. S., Bekaii-Saab, T. S., Barve, M., Saltzman, J., Sabari, J. K., Peguero, J. A., Paulson, A. S., Jänne, P. A., et al. (2024) · Cancer Discovery · doi:10.1158/2159-8290.cd-24-0217 · Cited by 139 · 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
Kuboki, Y., Fakih, M., Strickler, J., Yaeger, R., Masuishi, T., Kim, E. J., Bestvina, C. M., Kopetz, S., Falchook, G. S., Langer, C., et al. (2024) · Nature Medicine · doi:10.1038/s41591-023-02717-6 · Cited by 103 · cited 1× · see citing works
“In vivo studies showed that once-daily dosing of glecirasib can strongly inhibit p-ERK for at least 24 hours and induce maximal tumor responses agent alone in patients with colorectal cancer (36, 37).”
Tyrosyl phosphorylation of KRAS stalls GTPase cycle via alteration of switch I and II conformation
Kano, Y., Gebregiworgis, T., Marshall, C. B., Radulovich, N., Poon, B. P. K., St-Germain, J., Cook, J. D., Valencia-Sama, I., Grant, B. M. M., Herrera, S. G., et al. (2019) · Nature Communications · doi:10.1038/s41467-018-08115-8 · Cited by 103 · cited 2× · see citing works
“Considering the role of SHP2 to activate the RAS pathway through multiple modes of action, including the dephosphorylation of RAS and promoting SOS1 activity (31, 32), there is also strong rationale for the combination of KRAS G12C and SHP2 inhibitors.”
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
Stopping the beating heart of cancer: KRAS reviewed
Herdeis, L., Gerlach, D., McConnell, D. B., & Kessler, D. (2021) · Current Opinion in Structural Biology · doi:10.1016/j.sbi.2021.06.013 · Cited by 63 · see citing works
The effects of mutant Ras proteins on the cell signalome
Takács, T., Kudlik, G., Kurilla, A., Szeder, B., Buday, L., & Vas, V. (2020) · Cancer and Metastasis Reviews · doi:10.1007/s10555-020-09912-8 · Cited by 62 · see citing works
Zhou, Q. W., Meng, X., Sun, L., Huang, D., Yang, N., Yu, Y., Zhao, M., Zhuang, W., Guo, R., Hu, Y., et al. (2024) · Journal of Thoracic Oncology · doi:10.1016/j.jtho.2024.08.005 · Cited by 59 · see citing works
Vassella, E., Kashani, E., Zens, P., Kündig, A., Fung, C., Scherz, A., Herrmann, E., Ermiş, E., Schmid, R. A., & Berezowska, S. (2021) · European Journal of Cancer · doi:10.1016/j.ejca.2021.10.006 · Cited by 50 · see citing works
Li, Z., Dang, X., Huang, D., Jin, S., Li, W., Shi, J., Wang, X., Zhang, Y., Song, Z., Zhang, J., et al. (2024) · The Lancet Respiratory Medicine · doi:10.1016/s2213-2600(24)00110-3 · Cited by 49 · see citing works
Self-citationSotorasib Is a Pan- RAS G12C Inhibitor Capable of Driving Clinical Response in NRAS G12C Cancers
Rubinson, D. A., Tanaka, N., de la Cruz, F. F., Kapner, K. S., Rosenthal, M. H., Norden, B. L., Barnes, H., Ehnstrom, S., Morales-Giron, A. A., Brais, L. K., et al. (2024) · Cancer Discovery · doi:10.1158/2159-8290.cd-23-1138 · Cited by 46 · see citing works
Glecirasib in KRASG12C-mutated nonsmall-cell lung cancer: a phase 2b trial
Shi, Y., Fang, J., Xing, L., Yao, Y., Zhang, J., Liu, L., Wang, Y., Hu, C., Xiong, J., Liu, Z., et al. (2025) · Nature Medicine · doi:10.1038/s41591-024-03401-z · Cited by 42 · see citing works
Self-citationDiscovery of JAB-3312, a Potent SHP2 Allosteric Inhibitor for Cancer Treatment
Ma, C., Kang, D., Gao, P., Zhang, W., Wu, X.-P., Xu, Z., Han, H., Zhang, L., Cai, Y., Wang, Y., et al. (2024) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.4c00360 · Cited by 25 · see citing works
Self-citationWaterhouse, D. M., Rothschild, S. I., Dooms, C., Mennecier, B., Bozorgmehr, F., Majem, M., van den Heuvel, M. H., Linardou, H., Cho, B. C., Roberts‐Thomson, R., et al. (2024) · Lung Cancer · doi:10.1016/j.lungcan.2024.107921 · Cited by 20 · see citing works
Self-citationLi, A., Li, S., Wang, P. G., Dang, C., Fan, X. M., Chen, M., Liu, D., Li, F., Liu, H., Zhang, W., et al. (2025) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.4c02939 · Cited by 15 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
Al-Karmalawy, A. A., Eissa, M. E., Ashour, N. A., Yousef, T. A., Khatib, A. O. A., & Hawas, S. S. (2025) · RSC Advances · doi:10.1039/d5ra05472a · Cited by 38 · see citing works
Zhong, J., Zhao, J., Duan, J., Fang, J., Fei, K., Li, X., Chen, J., Wang, Z., Chu, Q., Yu, Y., et al. (2025) · The Lancet Respiratory Medicine · doi:10.1016/s2213-2600(25)00258-9 · Cited by 16 · see citing works
Self-citationAdvances on drug therapy for KRAS-mutant non-small-cell lung cancer
Tian, T., & Li, W. (2026) · Translational Oncology · doi:10.1016/j.tranon.2026.102668 · Cited by 4 · see citing works
Systematic and precise interventions for KRAS-mutant cancers
Liang, J., Wu, J., Zhang, Y., Wang, H., Zheng, Y., & He, Q. (2026) · Experimental Hematology and Oncology · doi:10.1186/s40164-026-00763-7 · Cited by 3 · see citing works
Optimization of Covalent 6-Cyanoquinazoline KRAS G12C Inhibitors for the Treatment of Solid Tumors
Waldo, J. P., Krawczuk, P. J., Kelly, C. B., Callas, C. G., Cisar, J. S., Eccles, W., Guerrero, C. A., Hack, M. D., Jones, W. M., Keohane, C. E., et al. (2026) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.5c03610
Drug repurposing in KRAS G12C-mutant NSCLC: a focus on resistance mechanisms and clinical strategies
Jain, A., Rosell, R., Dharmashekara, C., Shreevatsa, B., González-Cao, M., Shivakumar, A., Kollur, S. P., Prasad, A., Shivamallu, C., & Prasad, M. (2026) · Naunyn-Schmiedeberg s Archives of Pharmacology · doi:10.1007/s00210-026-05533-0
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Saadany, T. E., Aeschlimann, N., & Sacher, A. (2026) · The Cancer Journal · doi:10.1097/ppo.0000000000000842
Glecirasib treatment in KRAS G12C-positive non-small cell lung cancer with leptomeningeal metastasis
Li, Y., Wei, J., Li, M., Xu, T., Fang, S., & Liu, N. (2026) · Frontiers in Oncology · doi:10.3389/fonc.2026.1956344
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Hu, Y., He, F., He, C., Cao, C., Zhong, N., Yang, Z., & Li, Y. (2026) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2026.10.015
- Authors
- Wang, P., Sun, X., He, X., Kang, D., Liu, X., Liu, D., Li, A., Yang, G., Lin, Y., Li, S., Wang, Y., & Wang, Y.
- Affiliations
- 1Jacobio Pharmaceuticals Co., Ltd., Beijing, China.
- 2Jacobio (US) Pharmaceuticals, Inc., Burlington, Massachusetts.
- 3Jacobio Pharmaceuticals Group Co., Ltd., Beijing, China.
- Corresponding author
- Wang, Yanping
- ORCID
- Venue
- Cancer Research Communications
- Published
- 2025-05-01
- Volume
- 5
- Issue
- 5
- Pages
- 792-803
- ISSN
- 2767-9764 (ISSN-L)
- PMC
- PMC12076188
- OpenAlex
- W4409965407
- Cited by
- 9
- References
- 37
- Citations by year
- 2026: 7 · 2025: 2
- FWCI
- 2.71
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cancer Research Communications (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Keywords
- KRAS G12C, covalent KRAS inhibitor, SHP2 inhibition, cetuximab, EGFR inhibition, drug synergy, ERK1/2 phosphorylation, Akt phosphorylation, non-small cell lung cancer, intracranial xenograft
- MeSH terms
- Cetuximab, Animals, Antineoplastic Combined Chemotherapy Protocols, Drug Synergism, Humans, Mutation, Pyrimidines, Proto-Oncogene Proteins p21(ras), Apoptosis, Xenograft Model Antitumor Assays, Cell Line, Tumor, Mice, Protein Tyrosine Phosphatase, Non-Receptor Type 11
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