AMG-510 and cisplatin combination increases antitumor effect in lung adenocarcinoma with mutation of KRAS G12C: a preclinical and translational research
Abstract Background The efficacy of monotherapy of AMG-510 is limited. This study explored whether the AMG-510 and cisplatin combination increases the anti-tumor effect in lung adenocarcinoma with the mutation of Kirsten rat sarcoma viral oncogene (KRAS) G12C. Methods Patients’ data were used to ana...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Springer
2023-06-01
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| Series: | Discover Oncology |
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| Online Access: | https://doi.org/10.1007/s12672-023-00698-z |
| _version_ | 1827928602967015424 |
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| author | Lei-Lei Wu Wen-Mei Jiang Zhi-Yuan Liu Yi-Yi Zhang Jia-Yi Qian Yu’e Liu Yang-Yu Huang Kun Li Zhi-Xin Li Guo-Wei Ma Dong Xie |
| author_facet | Lei-Lei Wu Wen-Mei Jiang Zhi-Yuan Liu Yi-Yi Zhang Jia-Yi Qian Yu’e Liu Yang-Yu Huang Kun Li Zhi-Xin Li Guo-Wei Ma Dong Xie |
| author_sort | Lei-Lei Wu |
| collection | DOAJ |
| description | Abstract Background The efficacy of monotherapy of AMG-510 is limited. This study explored whether the AMG-510 and cisplatin combination increases the anti-tumor effect in lung adenocarcinoma with the mutation of Kirsten rat sarcoma viral oncogene (KRAS) G12C. Methods Patients’ data were used to analyze the proportion of KRAS G12C mutation. Besides, the next-generation sequencing data was used to uncover information about co-mutations. The cell viability assay, the concentration inhibiting 50% of cell viability (IC50) determination, colony formation, and cell-derived xenografts were conducted to explore the anti-tumor effect of AMG-510, Cisplatin, and their combination in vivo. The bioinformatic analysis was conducted to reveal the potential mechanism of drug combination with improved anticancer effect. Results The proportion of KRAS mutation was 2.2% (11/495). In this cohort with KRAS mutation, the proportion of G12D was higher than others. Besides, KRAS G12A mutated tumors had the likelihood of concurrent serine/threonine kinase 11 (STK11) and kelch-like ECH-associated protein 1 (KEAP1) mutations. KRAS G12C and tumor protein p53 (TP53) mutations could appear at the same time. In addition, KRAS G12D mutations and C-Ros oncogene 1 (ROS1) rearrangement were likely to be present in one tumor simultaneously. When the two drugs were combined, the respective IC50 values were lower than when used alone. In addition, there was a minimum number of clones among all wells in the drug combination. In in vivo experiments, the tumor size reduction in the drug combination group was more than twice that of the single drug group (p < 0.05). The differential expression genes were enriched in the pathways of phosphatidylinositol 3 kinase-protein kinase B (PI3K-Akt) signaling and extracellular matrix (ECM) proteoglycans compared the combination group to the control group. Conclusions The anticancer effect of the drug combination was confirmed to be better than monotherapy in vitro and in vivo. The results of this study may provide some information for the plan of neoadjuvant therapy and the design of clinical trials for lung adenocarcinoma patients with KRAS G12C mutation. |
| first_indexed | 2024-03-13T06:10:00Z |
| format | Article |
| id | doaj.art-01f33144faf6435d8ceb20f40eb096e5 |
| institution | Directory Open Access Journal |
| issn | 2730-6011 |
| language | English |
| last_indexed | 2024-03-13T06:10:00Z |
| publishDate | 2023-06-01 |
| publisher | Springer |
| record_format | Article |
| series | Discover Oncology |
| spelling | doaj.art-01f33144faf6435d8ceb20f40eb096e52023-06-11T11:17:35ZengSpringerDiscover Oncology2730-60112023-06-0114111510.1007/s12672-023-00698-zAMG-510 and cisplatin combination increases antitumor effect in lung adenocarcinoma with mutation of KRAS G12C: a preclinical and translational researchLei-Lei Wu0Wen-Mei Jiang1Zhi-Yuan Liu2Yi-Yi Zhang3Jia-Yi Qian4Yu’e Liu5Yang-Yu Huang6Kun Li7Zhi-Xin Li8Guo-Wei Ma9Dong Xie10Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji UniversityState Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer CenterSchool of Medicine, Tongji UniversitySchool of Medicine, Tongji UniversityDepartment of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji UniversitySchool of Medicine, Tongji UniversityFaculty of Biology, Medicine and Health, School of Biological Sciences, The University of ManchesterDepartment of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji UniversityDepartment of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji UniversityState Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer CenterDepartment of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji UniversityAbstract Background The efficacy of monotherapy of AMG-510 is limited. This study explored whether the AMG-510 and cisplatin combination increases the anti-tumor effect in lung adenocarcinoma with the mutation of Kirsten rat sarcoma viral oncogene (KRAS) G12C. Methods Patients’ data were used to analyze the proportion of KRAS G12C mutation. Besides, the next-generation sequencing data was used to uncover information about co-mutations. The cell viability assay, the concentration inhibiting 50% of cell viability (IC50) determination, colony formation, and cell-derived xenografts were conducted to explore the anti-tumor effect of AMG-510, Cisplatin, and their combination in vivo. The bioinformatic analysis was conducted to reveal the potential mechanism of drug combination with improved anticancer effect. Results The proportion of KRAS mutation was 2.2% (11/495). In this cohort with KRAS mutation, the proportion of G12D was higher than others. Besides, KRAS G12A mutated tumors had the likelihood of concurrent serine/threonine kinase 11 (STK11) and kelch-like ECH-associated protein 1 (KEAP1) mutations. KRAS G12C and tumor protein p53 (TP53) mutations could appear at the same time. In addition, KRAS G12D mutations and C-Ros oncogene 1 (ROS1) rearrangement were likely to be present in one tumor simultaneously. When the two drugs were combined, the respective IC50 values were lower than when used alone. In addition, there was a minimum number of clones among all wells in the drug combination. In in vivo experiments, the tumor size reduction in the drug combination group was more than twice that of the single drug group (p < 0.05). The differential expression genes were enriched in the pathways of phosphatidylinositol 3 kinase-protein kinase B (PI3K-Akt) signaling and extracellular matrix (ECM) proteoglycans compared the combination group to the control group. Conclusions The anticancer effect of the drug combination was confirmed to be better than monotherapy in vitro and in vivo. The results of this study may provide some information for the plan of neoadjuvant therapy and the design of clinical trials for lung adenocarcinoma patients with KRAS G12C mutation.https://doi.org/10.1007/s12672-023-00698-zKRAS G12C mutationAMG-510CisplatinIn vivoTranslational medicine |
| spellingShingle | Lei-Lei Wu Wen-Mei Jiang Zhi-Yuan Liu Yi-Yi Zhang Jia-Yi Qian Yu’e Liu Yang-Yu Huang Kun Li Zhi-Xin Li Guo-Wei Ma Dong Xie AMG-510 and cisplatin combination increases antitumor effect in lung adenocarcinoma with mutation of KRAS G12C: a preclinical and translational research Discover Oncology KRAS G12C mutation AMG-510 Cisplatin In vivo Translational medicine |
| title | AMG-510 and cisplatin combination increases antitumor effect in lung adenocarcinoma with mutation of KRAS G12C: a preclinical and translational research |
| title_full | AMG-510 and cisplatin combination increases antitumor effect in lung adenocarcinoma with mutation of KRAS G12C: a preclinical and translational research |
| title_fullStr | AMG-510 and cisplatin combination increases antitumor effect in lung adenocarcinoma with mutation of KRAS G12C: a preclinical and translational research |
| title_full_unstemmed | AMG-510 and cisplatin combination increases antitumor effect in lung adenocarcinoma with mutation of KRAS G12C: a preclinical and translational research |
| title_short | AMG-510 and cisplatin combination increases antitumor effect in lung adenocarcinoma with mutation of KRAS G12C: a preclinical and translational research |
| title_sort | amg 510 and cisplatin combination increases antitumor effect in lung adenocarcinoma with mutation of kras g12c a preclinical and translational research |
| topic | KRAS G12C mutation AMG-510 Cisplatin In vivo Translational medicine |
| url | https://doi.org/10.1007/s12672-023-00698-z |
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