The KRASG12C inhibitors in lung cancer therapy
DOI:
https://doi.org/10.12775/JEHS.2023.17.01.015Keywords
Lung cancer, targeted therapies, KRAS mutationAbstract
Introduction:
Lung cancer is characterized by the highest mortality among cancers and is the second most frequently diagnosed type of cancer in the world.
Targeted therapies are a promising therapeutic option for patients with this disease, however, one of the most common and most malignant mutations (KRAS) remains a challenge.
Purpose:
The aim of this study is to bring closer the problem of the KRAS mutation, in particular KRASG12C, and to present the most important information about the compounds created for therapies targeted at it.
For a better understanding of the issue, the study contains information about the mechanisms of both mutation and drugs, as well as the most important statistical data and research results.
Materials and methods:
The review was based on articles available in the PubMed database.
Conclusions:
Two drugs targeting KRASG12C (sotorasib and adagrasib) have proven their clinical effectiveness and represent a milestone in the development of targeted therapies for lung cancer with this mutation.
However, they are not without side effects, and the emerging resistance and presence of commutations that reduce drug potency continue to challenge the scientific community.
Research is underway to refine therapies using existing inhibitors as well as to develop further compounds targeting KRASG12C.
References
Reck M, Carbone DP, Garassino M, Barlesi F. Targeting KRAS in non-small-cell lung cancer: recent progress and new approaches. Ann Oncol. 2021 Sep;32(9):1101-1110. doi: 10.1016/j.annonc.2021.06.001. Epub 2021 Jun 2. PMID: 34089836.
Ferrer I, Zugazagoitia J, Herbertz S, John W, Paz-Ares L, Schmid-Bindert G. KRAS-Mutant non-small cell lung cancer: From biology to therapy. Lung Cancer. 2018 Oct;124:53-64. doi: 10.1016/j.lungcan.2018.07.013. Epub 2018 Jul 19. PMID: 30268480.
Rodak O, Peris-Díaz MD, Olbromski M, Podhorska-Okołów M, Dzięgiel P. Current Landscape of Non-Small Cell Lung Cancer: Epidemiology, Histological Classification, Targeted Therapies, and Immunotherapy. Cancers (Basel). 2021 Sep 20;13(18):4705. doi: 10.3390/cancers13184705. PMID: 34572931; PMCID: PMC8470525.
Moore AR, Rosenberg SC, McCormick F, Malek S. RAS-targeted therapies: is the undruggable drugged? Nat Rev Drug Discov. 2020 Aug;19(8):533-552. doi: 10.1038/s41573-020-0068-6. Epub 2020 Jun 11. Erratum in: Nat Rev Drug Discov. 2020 Dec;19(12):902. PMID: 32528145; PMCID: PMC7809886.
Ghimessy A, Radeczky P, Laszlo V, Hegedus B, Renyi-Vamos F, Fillinger J, Klepetko W, Lang C, Dome B, Megyesfalvi Z. Current therapy of KRAS-mutant lung cancer. Cancer Metastasis Rev. 2020 Dec;39(4):1159-1177. doi: 10.1007/s10555-020-09903-9. PMID: 32548736; PMCID: PMC7680319.
Lee A. Sotorasib: A Review in KRAS G12C Mutation-Positive Non-small Cell Lung Cancer. Target Oncol. 2022 Nov;17(6):727-733. doi: 10.1007/s11523-022-00922-w. Epub 2022 Oct 31. Erratum in: Target Oncol. 2022 Dec 2;: PMID: 36315377; PMCID: PMC9715446.
Nakajima EC, Drezner N, Li X, Mishra-Kalyani PS, Liu Y, Zhao H, Bi Y, Liu J, Rahman A, Wearne E, Ojofeitimi I, Hotaki LT, Spillman D, Pazdur R, Beaver JA, Singh H. FDA Approval Summary: Sotorasib for KRAS G12C-Mutated Metastatic NSCLC. Clin Cancer Res. 2022 Apr 14;28(8):1482-1486. doi: 10.1158/1078-0432.CCR-21-3074. PMID: 34903582; PMCID: PMC9012672.
Ou SI, Jänne PA, Leal TA, Rybkin II, Sabari JK, Barve MA, Bazhenova L, Johnson ML, Velastegui KL, Cilliers C, Christensen JG, Yan X, Chao RC, Papadopoulos KP. First-in-Human Phase I/IB Dose-Finding Study of Adagrasib (MRTX849) in Patients With Advanced KRASG12C Solid Tumors (KRYSTAL-1). J Clin Oncol. 2022 Aug 10;40(23):2530-2538. doi: 10.1200/JCO.21.02752. Epub 2022 Feb 15. PMID: 35167329; PMCID: PMC9362872.
Sabari JK, Velcheti V, Shimizu K, Strickland MR, Heist RS, Singh M, Nayyar N, Giobbie-Hurder A, Digumarthy SR, Gainor JF, Rajan AP, Nieblas-Bedolla E, Burns AC, Hallin J, Olson P, Christensen JG, Kurz SC, Brastianos PK, Wakimoto H. Activity of Adagrasib (MRTX849) in Brain Metastases: Preclinical Models and Clinical Data from Patients with KRASG12C-Mutant Non-Small Cell Lung Cancer. Clin Cancer Res. 2022 Aug 2;28(15):3318-3328. doi: 10.1158/1078-0432.CCR-22-0383. PMID: 35404402; PMCID: PMC9662862.
Dhillon S. Adagrasib: First Approval. Drugs. 2023 Feb;83(3):275-285. doi: 10.1007/s40265-023-01839-y. PMID: 36763320.
Patricelli MP, Janes MR, Li LS, Hansen R, Peters U, Kessler LV, Chen Y, Kucharski JM, Feng J, Ely T, Chen JH, Firdaus SJ, Babbar A, Ren P, Liu Y. Selective Inhibition of Oncogenic KRAS Output with Small Molecules Targeting the Inactive State. Cancer Discov. 2016 Mar;6(3):316-29. doi: 10.1158/2159-8290.CD-15-1105. Epub 2016 Jan 6. PMID: 26739882.
Sutton MN, Gammon ST, Muzzioli R, Pisaneschi F, Radaram B, Yang P, Piwnica-Worms D. RAS-Driven Macropinocytosis of Albumin or Dextran Reveals Mutation-Specific Target Engagement of RAS p.G12C Inhibitor ARS-1620 by NIR-Fluorescence Imaging. Mol Imaging Biol. 2022 Jun;24(3):498-509. doi: 10.1007/s11307-021-01689-8. Epub 2021 Dec 14. PMID: 34905147; PMCID: PMC9090937.
Blaquier JB, Cardona AF, Recondo G. Resistance to KRASG12C Inhibitors in Non-Small Cell Lung Cancer. Front Oncol. 2021 Dec 24;11:787585. doi: 10.3389/fonc.2021.787585. PMID: 35004309; PMCID: PMC8739760.
Zhang J, Johnson M, Barve M, Bazhenova L, McCarthy M, Schwartz R, Horvath-Walsh E, Velastegui K, Qian C, Spira A. Practical Guidance for the Management of Adverse Events in Patients with KRASG12C-Mutated Non-Small Cell Lung Cancer Receiving Adagrasib. Oncologist. 2023 Apr 6;28(4):287-296. doi: 10.1093/oncolo/oyad051. PMID: 36892150; PMCID: PMC10078892.
Jänne PA, Riely GJ, Gadgeel SM, Heist RS, Ou SI, Pacheco JM, Johnson ML, Sabari JK, Leventakos K, Yau E, Bazhenova L, Negrao MV, Pennell NA, Zhang J, Anderes K, Der-Torossian H, Kheoh T, Velastegui K, Yan X, Christensen JG, Chao RC, Spira AI. Adagrasib in Non-Small-Cell Lung Cancer Harboring a KRASG12C Mutation. N Engl J Med. 2022 Jul 14;387(2):120-131. doi: 10.1056/NEJMoa2204619. Epub 2022 Jun 3. PMID: 35658005.
TRAE - zdarzenia niepożądane 3-5 stopnia związane z leczeniem
Janes MR, Zhang J, Li LS, Hansen R, Peters U, Guo X, Chen Y, Babbar A, Firdaus SJ, Darjania L, Feng J, Chen JH, Li S, Li S, Long YO, Thach C, Liu Y, Zarieh A, Ely T, Kucharski JM, Kessler LV, Wu T, Yu K, Wang Y, Yao Y, Deng X, Zarrinkar PP, Brehmer D, Dhanak D, Lorenzi MV, Hu-Lowe D, Patricelli MP, Ren P, Liu Y. Targeting KRAS Mutant Cancers with a Covalent G12C-Specific Inhibitor. Cell. 2018 Jan 25;172(3):578-589.e17. doi: 10.1016/j.cell.2018.01.006. PMID: 29373830.
Koga T, Suda K, Fujino T, Ohara S, Hamada A, Nishino M, Chiba M, Shimoji M, Takemoto T, Arita T, Gmachl M, Hofmann MH, Soh J, Mitsudomi T. KRAS Secondary Mutations That Confer Acquired Resistance to KRAS G12C Inhibitors, Sotorasib and Adagrasib, and Overcoming Strategies: Insights From In Vitro Experiments. J Thorac Oncol. 2021 Aug;16(8):1321-1332. doi: 10.1016/j.jtho.2021.04.015. Epub 2021 May 7. PMID: 33971321.
Dunnett-Kane V, Nicola P, Blackhall F, Lindsay C. Mechanisms of Resistance to KRASG12C Inhibitors. Cancers (Basel). 2021 Jan 5;13(1):151. doi: 10.3390/cancers13010151. PMID: 33466360; PMCID: PMC7795113.
Kotecha R, La Rosa A, Kutuk T, Ahluwalia MS, Mehta MP. Evaluating the intracranial activity of adagrasib. Transl Lung Cancer Res. 2023 Apr 28;12(4):669-675. doi: 10.21037/tlcr-23-74. Epub 2023 Apr 4. PMID: 37197630; PMCID: PMC10183405.
Zhang SS, Nagasaka M. Spotlight on Sotorasib (AMG 510) for KRASG12C Positive Non-Small Cell Lung Cancer. Lung Cancer (Auckl). 2021 Oct 7;12:115-122. doi: 10.2147/LCTT.S334623. PMID: 34675734; PMCID: PMC8504654.
Corral de la Fuente E, Olmedo Garcia ME, Gomez Rueda A, Lage Y, Garrido P. Targeting KRAS in Non-Small Cell Lung Cancer. Front Oncol. 2022 Jan 10;11:792635. doi: 10.3389/fonc.2021.792635. PMID: 35083149; PMCID: PMC8784727.
Downloads
Published
How to Cite
Issue
Section
License
Copyright (c) 2023 Maciej Jędrak, Karolina Niekurzak, Joanna Kania, Maciej Józefiak, Piotr Sobkiewicz, Krzysztof Kania
![Creative Commons License](http://i.creativecommons.org/l/by-nc-sa/4.0/88x31.png)
This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.
The periodical offers access to content in the Open Access system under the Creative Commons Attribution-NonCommercial-ShareAlike 4.0
Stats
Number of views and downloads: 233
Number of citations: 0