A Review of KRAS Inhibitors and Potential Improvement in The Future

Ziyan Jiang

doi:10.62051/23mxsn86

Authors

Ziyan Jiang

DOI:

https://doi.org/10.62051/23mxsn86

Keywords:

tumor; KRAS inhibitor; KRASi resistance; small interfering RNA; PanRAS inhibitor.

Abstract

Kirsten rat sarcoma viral (KRAS) oncogene is one of the most common mutant genes in tumors, especially in non-small cell lung cancer, colorectal cancer, and pancreatic cancer. In recent years, great success was achieved in targeting KRAS for the treatment of tumors. So far, two drugs, sotorasib and adagrasib, have gotten through the accelerated approval by the FDA. Even so, current treatments are still far from satisfaction due to the inevitable acquired drug resistance and the diversity of mutant isoforms. Various approaches are being investigated to address these issues, including the combination of multiple medications and the development of drugs with more targets. Overall, targeting KRAS is a promising and effective strategy for the treatment of cancer. For this reason, the article aims at introducing several representative KRAS-targeting drugs and exhibiting the latest research progress. Discussions about the acquired resistance and the potential solutions are also included, hoping to provide inspiration for the development and improvement of new drugs.

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References

[1] Y. Shang, S. Fu, Q. Hao, H. Ying, J. Wang, T. Shen, Multiple medicinal chemistry strategies of targeting KRAS: State-of-the art and future directions, Bioorganic chemistry, 144 (2024), 107092.

[2] W. H. Hsu, K. A. LaBella, Y. Lin, P. Xu, R. Lee, C. E. Hsieh, L. Yang, A. Zhou, J. M. Blecher, C. J. Wu, K. Lin, X. Shang, S. Jiang, D. J. Spring, Y. Xia, P. Chen, J. P. Shen, S. Kopetz, R. A. DePinho, Oncogenic KRAS Drives Lipofibrogenesis to Promote Angiogenesis and Colon Cancer Progression, Cancer Discovery, 13 (2023), 2652–2673.

[3] F. Skoulidis, B. T. Li, G. K. Dy, T. J. Price, G. S. Falchook, J. Wolf, A. Italiano, M. Schuler, H. Borghaei, F. Barlesi, T. Kato, A. Curioni-Fontecedro, A. Sacher, A. Spira, S. S. Ramalingam, T. Takahashi, B. Besse, A. Anderson, A. Ang, Q. Tran, R. Govindan, Sotorasib for Lung Cancers with KRAS p.G12C Mutation, The New England Journal of Medicine, 384 (2021), 2371–2381.

[4] A. J. de Langen, M. L. Johnson, J. Mazieres, A. C. Dingemans, G. Mountzios, M. Pless, J. Wolf, M. Schuler, H. Lena, F. Skoulidis, Y. Yoneshima, S. W. Kim, H. Linardou, S. Novello, A. J. van der Wekken, Y. Chen, S. Peters, E. Felip, B. J. Solomon, S. S. Ramalingam, CodeBreaK 200 Investigators, Sotorasib versus Docetaxel for Previously Treated Non-Small-Cell Lung Cancer with KRASG12C Mutation: A Randomised, Open-Label, Phase 3 Trial, Lancet (London, England), 401 (2023), 733–746.

[5] A. Fraissenon, C. Bayard, G. Morin, S. Benichi, C. Hoguin, S. Protic, L. Zerbib, S. Ladraa, M. Firpion, T. Blauwblomme, O. Naggara, M. Duruisseaux, M. Delous, C. Boitel, P. P. Bringuier, L. Payen, C. Legendre, S. Kaltenbach, E. Balducci, P. Villarese, G. Canaud, Sotorasib for Vascular Malformations Associated with KRAS G12C Mutation, The New England Journal of Medicine, 391 (2024), 334–342.

[6] P. A. Jänne, G. J. Riely, S. M. Gadgeel, R. S. Heist, S. I. Ou, J. M. Pacheco, M. L. Johnson, J. K. Sabari, K. Leventakos, E. Yau, L. Bazhenova, M. V. Negrao, N. A. Pennell, J. Zhang, K. Anderes, H. Der-Torossian, T. Kheoh, K. Velastegui, X. Yan, J. G. Christensen, ... A. I. Spira, Adagrasib in Non-Small-Cell Lung Cancer Harboring a KRASG12C Mutation, The New England Journal of Medicine, 387 (2022), 120–131.

[7] R. Yaeger, J. Weiss, M. S. Pelster, A. I. Spira, M. Barve, S. I. Ou, T. A. Leal, T. S. Bekaii-Saab, C. P. Paweletz, G. A. Heavey, J. G. Christensen, K. Velastegui, T. Kheoh, H. Der-Torossian, S. J. Klempner, Adagrasib with or without Cetuximab in Colorectal Cancer with Mutated KRAS G12C, The New England Journal of Medicine, 388 (2023), 44–54.

[8] A. Sacher, P. LoRusso, M. R. Patel, W. H. Miller Jr, E. Garralda, M. D. Forster, A. Santoro, A. Falcon, T. W. Kim, L. Paz-Ares, S. Bowyer, M. de Miguel, S. W. Han, M. G. Krebs, J. S. Lee, M. L. Cheng, K. Arbour, E. Massarelli, Y. Choi, Z. Shi, GO42144 Investigator and Study Group, Single-Agent Divarasib (GDC-6036) in Solid Tumors with a KRAS G12C Mutation, The New England Journal of Medicine, 389 (2023), 710–721.

[9] J. M. Ketcham, J. Haling, S. Khare, V. Bowcut, D. M. Briere, A. C. Burns, R. J. Gunn, A. Ivetac, J. Kuehler, S. Kulyk, J. Laguer, J. D. Lawson, K. Moya, N. Nguyen, L. Rahbaek, B. Saechao, C. R. Smith, N. C. Sudhakar, L. Vegar, M. A. Marx, Design and Discovery of MRTX0902, a Potent, Selective, Brain-Penetrant, and Orally Bioavailable Inhibitor of the SOS1 Protein-Protein Interaction, Journal of Medicinal Chemistry, 65 (2022), 9678–9690.

[10] J. Hallin, V. Bowcut, A. Calinisan, D. M. Briere, L. Hargis, L. D. Engstrom, J. Laguer, J. Medwid, D. Vanderpool, E. Lifset, D. Trinh, N. Hoffman, X. Wang, J. D. Lawson, R. J. Gunn, C. R. Smith, N. C. Thomas, M. Martinson, A. Bergstrom, F. Sullivan, J. G. Christensen, Anti-Tumor Efficacy of a Potent and Selective Non-Covalent KRASG12D Inhibitor, Nature Medicine, 28 (2022), 2171–2182.

[11] J. Jiang, L. Jiang, B. J. Maldonato, Y. Wang, M. Holderfield, I. Aronchik, I. Winters, Z. Salman, C. Blaj, M. Menard, J. Brodbeck, Z. Chen, X. Wei, M. J. Rosen, Y. Gindin, B. J. Lee, J. W. Evans, S. Chang, Z. Wang, K. J. Seamon, M. Singh, Translational and Therapeutic Evaluation of RAS-GTP Inhibition by RMC-6236 in RAS-Driven Cancers, Cancer Discovery, 14 (2024), 994–1017.

[12] X. Lv, X. Lu, J. Cao, Q. Luo, Y. Ding, F. Peng, A. Pataer, D. Lu, D. Han, E. Malmberg, D. W. Chan, X. Wang, S. R. Savage, S. Mao, J. Yu, F. Peng, L. Yan, H. Meng, L. Maneix, Y. Han, X. Chen, Modulation of the Proteostasis Network Promotes Tumor Resistance to Oncogenic KRAS Inhibitors, Science (New York, N.Y.), 381 (2023), eabn4180.

[13] Y. Kuboki, M. Fakih, J. Strickler, R. Yaeger, T. Masuishi, E. J. Kim, C. M. Bestvina, S. Kopetz, G. S. Falchook, C. Langer, J. Krauss, S. Puri, P. Cardona, E. Chan, T. Varrieur, L. Mukundan, A. Anderson, Q. Tran, D. S. Hong, Sotorasib with Panitumumab in Chemotherapy-Refractory KRASG12C-Mutated Colorectal Cancer: A Phase 1b Trial, Nature Medicine, 30 (2024), 265–270.