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Targeting Mutant Kirsten Rat Sarcoma Viral Oncogene Homolog in Non-Small Cell Lung Cancer: Current Difficulties, Integrative Treatments and Future Perspectives

In the past few decades, several gene mutations, including the anaplastic lymphoma kinase, epidermal growth factor receptor, ROS proto-oncogene 1 and rat sarcoma viral oncogene homolog (RAS), have been discovered in non-small cell lung cancer (NSCLC). Kirsten rat sarcoma viral oncogene homolog (KRAS...

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Autores principales: Li, Jia-Xin, Li, Run-Ze, Ma, Lin-Rui, Wang, Peng, Xu, Dong-Han, Huang, Jie, Li, Li-Qi, Tang, Ling, Xie, Ying, Leung, Elaine Lai-Han, Yan, Pei-Yu
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9065471/
https://www.ncbi.nlm.nih.gov/pubmed/35517800
http://dx.doi.org/10.3389/fphar.2022.875330
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author Li, Jia-Xin
Li, Run-Ze
Ma, Lin-Rui
Wang, Peng
Xu, Dong-Han
Huang, Jie
Li, Li-Qi
Tang, Ling
Xie, Ying
Leung, Elaine Lai-Han
Yan, Pei-Yu
author_facet Li, Jia-Xin
Li, Run-Ze
Ma, Lin-Rui
Wang, Peng
Xu, Dong-Han
Huang, Jie
Li, Li-Qi
Tang, Ling
Xie, Ying
Leung, Elaine Lai-Han
Yan, Pei-Yu
author_sort Li, Jia-Xin
collection PubMed
description In the past few decades, several gene mutations, including the anaplastic lymphoma kinase, epidermal growth factor receptor, ROS proto-oncogene 1 and rat sarcoma viral oncogene homolog (RAS), have been discovered in non-small cell lung cancer (NSCLC). Kirsten rat sarcoma viral oncogene homolog (KRAS) is the isoform most frequently altered in RAS-mutated NSCLC cases. Due to the structural and biochemical characteristics of the KRAS protein, effective approaches to treating KRAS-mutant NSCLC still remain elusive. Extensive recent research on KRAS-mutant inhibitors has made a breakthrough in identifying the covalent KRAS(G12C) inhibitor as an effective agent for the treatment of NSCLC. This review mainly concentrated on introducing new covalent KRAS(G12C) inhibitors like sotorasib (AMG 510) and adagrasib (MRTX 849); summarizing inhibitors targeting the KRAS-related upstream and downstream effectors in RAF/MEK/ERK pathway and PI3K/AKT/mTOR pathway; exploring the efficacy of immunotherapy and certain emerging immune-related therapeutics such as adoptive cell therapy and cancer vaccines. These inhibitors are being investigated in clinical trials and have exhibited promising effects. On the other hand, naturally extracted compounds, which have exhibited safe and effective properties in treating KRAS-mutant NSCLC through suppressing the MAPK and PI3K/AKT/mTOR signaling pathways, as well as through decreasing PD-L1 expression in preclinical studies, could be expected to enter into clinical studies. Finally, in order to confront the matter of drug resistance, the ongoing clinical trials in combination treatment strategies were summarized herein.
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spelling pubmed-90654712022-05-04 Targeting Mutant Kirsten Rat Sarcoma Viral Oncogene Homolog in Non-Small Cell Lung Cancer: Current Difficulties, Integrative Treatments and Future Perspectives Li, Jia-Xin Li, Run-Ze Ma, Lin-Rui Wang, Peng Xu, Dong-Han Huang, Jie Li, Li-Qi Tang, Ling Xie, Ying Leung, Elaine Lai-Han Yan, Pei-Yu Front Pharmacol Pharmacology In the past few decades, several gene mutations, including the anaplastic lymphoma kinase, epidermal growth factor receptor, ROS proto-oncogene 1 and rat sarcoma viral oncogene homolog (RAS), have been discovered in non-small cell lung cancer (NSCLC). Kirsten rat sarcoma viral oncogene homolog (KRAS) is the isoform most frequently altered in RAS-mutated NSCLC cases. Due to the structural and biochemical characteristics of the KRAS protein, effective approaches to treating KRAS-mutant NSCLC still remain elusive. Extensive recent research on KRAS-mutant inhibitors has made a breakthrough in identifying the covalent KRAS(G12C) inhibitor as an effective agent for the treatment of NSCLC. This review mainly concentrated on introducing new covalent KRAS(G12C) inhibitors like sotorasib (AMG 510) and adagrasib (MRTX 849); summarizing inhibitors targeting the KRAS-related upstream and downstream effectors in RAF/MEK/ERK pathway and PI3K/AKT/mTOR pathway; exploring the efficacy of immunotherapy and certain emerging immune-related therapeutics such as adoptive cell therapy and cancer vaccines. These inhibitors are being investigated in clinical trials and have exhibited promising effects. On the other hand, naturally extracted compounds, which have exhibited safe and effective properties in treating KRAS-mutant NSCLC through suppressing the MAPK and PI3K/AKT/mTOR signaling pathways, as well as through decreasing PD-L1 expression in preclinical studies, could be expected to enter into clinical studies. Finally, in order to confront the matter of drug resistance, the ongoing clinical trials in combination treatment strategies were summarized herein. Frontiers Media S.A. 2022-04-20 /pmc/articles/PMC9065471/ /pubmed/35517800 http://dx.doi.org/10.3389/fphar.2022.875330 Text en Copyright © 2022 Li, Li, Ma, Wang, Xu, Huang, Li, Tang, Xie, Leung and Yan. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Li, Jia-Xin
Li, Run-Ze
Ma, Lin-Rui
Wang, Peng
Xu, Dong-Han
Huang, Jie
Li, Li-Qi
Tang, Ling
Xie, Ying
Leung, Elaine Lai-Han
Yan, Pei-Yu
Targeting Mutant Kirsten Rat Sarcoma Viral Oncogene Homolog in Non-Small Cell Lung Cancer: Current Difficulties, Integrative Treatments and Future Perspectives
title Targeting Mutant Kirsten Rat Sarcoma Viral Oncogene Homolog in Non-Small Cell Lung Cancer: Current Difficulties, Integrative Treatments and Future Perspectives
title_full Targeting Mutant Kirsten Rat Sarcoma Viral Oncogene Homolog in Non-Small Cell Lung Cancer: Current Difficulties, Integrative Treatments and Future Perspectives
title_fullStr Targeting Mutant Kirsten Rat Sarcoma Viral Oncogene Homolog in Non-Small Cell Lung Cancer: Current Difficulties, Integrative Treatments and Future Perspectives
title_full_unstemmed Targeting Mutant Kirsten Rat Sarcoma Viral Oncogene Homolog in Non-Small Cell Lung Cancer: Current Difficulties, Integrative Treatments and Future Perspectives
title_short Targeting Mutant Kirsten Rat Sarcoma Viral Oncogene Homolog in Non-Small Cell Lung Cancer: Current Difficulties, Integrative Treatments and Future Perspectives
title_sort targeting mutant kirsten rat sarcoma viral oncogene homolog in non-small cell lung cancer: current difficulties, integrative treatments and future perspectives
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9065471/
https://www.ncbi.nlm.nih.gov/pubmed/35517800
http://dx.doi.org/10.3389/fphar.2022.875330
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