Improvement of ACK1-targeted therapy efficacy in lung adenocarcinoma using chloroquine or bafilomycin A1
Abstract Background Activated Cdc42-associated kinase 1 (ACK1) is a promising druggable target for cancer, but its inhibitors only showed moderate effects in clinical trials. The study aimed to investigate the underlying mechanisms and improve the antitumor efficacy of ACK1 inhibitors. Methods RNA-s...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2023-01-01
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| Series: | Molecular Medicine |
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| Online Access: | https://doi.org/10.1186/s10020-023-00602-z |
| _version_ | 1797945911677026304 |
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| author | Jinhong Zhu Kui Cao Meng Zhao Keru Ma Xiangyu Jiang Yuwen Bai Xiaodong Ling Jianqun Ma |
| author_facet | Jinhong Zhu Kui Cao Meng Zhao Keru Ma Xiangyu Jiang Yuwen Bai Xiaodong Ling Jianqun Ma |
| author_sort | Jinhong Zhu |
| collection | DOAJ |
| description | Abstract Background Activated Cdc42-associated kinase 1 (ACK1) is a promising druggable target for cancer, but its inhibitors only showed moderate effects in clinical trials. The study aimed to investigate the underlying mechanisms and improve the antitumor efficacy of ACK1 inhibitors. Methods RNA-seq was performed to determine the downstream pathways of ACK. Using Lasso Cox regression analysis, we built a risk signature with ACK1-related autophagy genes in the lung adenocarcinoma (LUAD) patients from The Cancer Genome Atlas (TCGA) project. The performance of the signature in predicting the tumor immune environment and response to immunotherapy and chemotherapy were assessed in LUAD. CCK8, mRFP-GFP-LC3 assay, western blot, colony formation, wound healing, and transwell migration assays were conducted to evaluate the effects of the ACK1 inhibitor on lung cancer cells. A subcutaneous NSCLC xenograft model was used for in vivo study. Results RNA-seq revealed the regulatory role of ACK1 in autophagy. Furthermore, the risk signature separated LUAD patients into low- and high-risk groups with significantly different prognoses. The two groups displayed different tumor immune environments regarding 28 immune cell subsets. The low-risk groups showed high immune scores, high CTLA4 expression levels, high immunophenoscore, and low DNA mismatch repair capacity, suggesting a better response to immunotherapy. This signature also predicted sensitivity to commonly used chemotherapy and targeted drugs. In vitro, the ACK1 inhibitors (AIM-100 and Dasatinib) appeared to trigger adaptive autophagy-like response to protect lung cancer cells from apoptosis and activated the AMPK/mTOR signaling pathway, partially explaining its moderate antitumor efficacy. However, blocking lysosomal degradation with chloroquine/Bafilamycine A1 or inhibiting AMPK signaling with compound C/shPRKAA1 enhanced the ACK1 inhibitor’s cytotoxic effects on lung cancer cells. The efficacy of the combined therapy was also verified using a mouse xenograft model. Conclusions The resulting signature from ACK1-related autophagy genes robustly predicted survival and drug sensitivity in LUAD. The lysosomal degradation inhibition improved the therapeutic effects of the ACK1 inhibitor, suggesting a potential role for autophagy in therapy evasion. |
| first_indexed | 2024-04-10T21:02:36Z |
| format | Article |
| id | doaj.art-e20f85885d614674838f07016a61b49c |
| institution | Directory Open Access Journal |
| issn | 1528-3658 |
| language | English |
| last_indexed | 2024-04-10T21:02:36Z |
| publishDate | 2023-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Medicine |
| spelling | doaj.art-e20f85885d614674838f07016a61b49c2023-01-22T12:17:03ZengBMCMolecular Medicine1528-36582023-01-0129112110.1186/s10020-023-00602-zImprovement of ACK1-targeted therapy efficacy in lung adenocarcinoma using chloroquine or bafilomycin A1Jinhong Zhu0Kui Cao1Meng Zhao2Keru Ma3Xiangyu Jiang4Yuwen Bai5Xiaodong Ling6Jianqun Ma7Department of Clinical Laboratory, Biobank, Harbin Medical University Cancer HospitalDepartment of Thoracic Surgery, Harbin Medical University Cancer HospitalDepartment of Clinical Laboratory, Biobank, Harbin Medical University Cancer HospitalDepartment of Thoracic Surgery, Harbin Medical University Cancer HospitalDepartment of Thoracic Surgery, Harbin Medical University Cancer HospitalDepartment of Thoracic Surgery, Harbin Medical University Cancer HospitalDepartment of Thoracic Surgery, Harbin Medical University Cancer HospitalDepartment of Thoracic Surgery, Harbin Medical University Cancer HospitalAbstract Background Activated Cdc42-associated kinase 1 (ACK1) is a promising druggable target for cancer, but its inhibitors only showed moderate effects in clinical trials. The study aimed to investigate the underlying mechanisms and improve the antitumor efficacy of ACK1 inhibitors. Methods RNA-seq was performed to determine the downstream pathways of ACK. Using Lasso Cox regression analysis, we built a risk signature with ACK1-related autophagy genes in the lung adenocarcinoma (LUAD) patients from The Cancer Genome Atlas (TCGA) project. The performance of the signature in predicting the tumor immune environment and response to immunotherapy and chemotherapy were assessed in LUAD. CCK8, mRFP-GFP-LC3 assay, western blot, colony formation, wound healing, and transwell migration assays were conducted to evaluate the effects of the ACK1 inhibitor on lung cancer cells. A subcutaneous NSCLC xenograft model was used for in vivo study. Results RNA-seq revealed the regulatory role of ACK1 in autophagy. Furthermore, the risk signature separated LUAD patients into low- and high-risk groups with significantly different prognoses. The two groups displayed different tumor immune environments regarding 28 immune cell subsets. The low-risk groups showed high immune scores, high CTLA4 expression levels, high immunophenoscore, and low DNA mismatch repair capacity, suggesting a better response to immunotherapy. This signature also predicted sensitivity to commonly used chemotherapy and targeted drugs. In vitro, the ACK1 inhibitors (AIM-100 and Dasatinib) appeared to trigger adaptive autophagy-like response to protect lung cancer cells from apoptosis and activated the AMPK/mTOR signaling pathway, partially explaining its moderate antitumor efficacy. However, blocking lysosomal degradation with chloroquine/Bafilamycine A1 or inhibiting AMPK signaling with compound C/shPRKAA1 enhanced the ACK1 inhibitor’s cytotoxic effects on lung cancer cells. The efficacy of the combined therapy was also verified using a mouse xenograft model. Conclusions The resulting signature from ACK1-related autophagy genes robustly predicted survival and drug sensitivity in LUAD. The lysosomal degradation inhibition improved the therapeutic effects of the ACK1 inhibitor, suggesting a potential role for autophagy in therapy evasion.https://doi.org/10.1186/s10020-023-00602-zACK1LUADChloroquineBafilomycin A1AMPKPrognosis |
| spellingShingle | Jinhong Zhu Kui Cao Meng Zhao Keru Ma Xiangyu Jiang Yuwen Bai Xiaodong Ling Jianqun Ma Improvement of ACK1-targeted therapy efficacy in lung adenocarcinoma using chloroquine or bafilomycin A1 Molecular Medicine ACK1 LUAD Chloroquine Bafilomycin A1 AMPK Prognosis |
| title | Improvement of ACK1-targeted therapy efficacy in lung adenocarcinoma using chloroquine or bafilomycin A1 |
| title_full | Improvement of ACK1-targeted therapy efficacy in lung adenocarcinoma using chloroquine or bafilomycin A1 |
| title_fullStr | Improvement of ACK1-targeted therapy efficacy in lung adenocarcinoma using chloroquine or bafilomycin A1 |
| title_full_unstemmed | Improvement of ACK1-targeted therapy efficacy in lung adenocarcinoma using chloroquine or bafilomycin A1 |
| title_short | Improvement of ACK1-targeted therapy efficacy in lung adenocarcinoma using chloroquine or bafilomycin A1 |
| title_sort | improvement of ack1 targeted therapy efficacy in lung adenocarcinoma using chloroquine or bafilomycin a1 |
| topic | ACK1 LUAD Chloroquine Bafilomycin A1 AMPK Prognosis |
| url | https://doi.org/10.1186/s10020-023-00602-z |
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