Integrating cfDNA liquid biopsy and organoid-based drug screening reveals PI3K signaling as a promising therapeutic target in colorectal cancer
Abstract Background The current precision medicine relies on biomarkers, which are mainly obtained through next-generation sequencing (NGS). However, this model failed to find effective drugs for most cancer patients. This study tried to combine liquid biopsy with functional drug tests using organoi...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2024-02-01
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| Series: | Journal of Translational Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12967-023-04675-6 |
| _version_ | 1797273389721714688 |
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| author | Huan Yang Xing Xiao Leli Zeng Haiteng Zeng Yueyuan Zheng Jingshu Wang Guanghua Li Weigang Dai Yulong He Suihai Wang Jianjun Peng Wei Chen |
| author_facet | Huan Yang Xing Xiao Leli Zeng Haiteng Zeng Yueyuan Zheng Jingshu Wang Guanghua Li Weigang Dai Yulong He Suihai Wang Jianjun Peng Wei Chen |
| author_sort | Huan Yang |
| collection | DOAJ |
| description | Abstract Background The current precision medicine relies on biomarkers, which are mainly obtained through next-generation sequencing (NGS). However, this model failed to find effective drugs for most cancer patients. This study tried to combine liquid biopsy with functional drug tests using organoid models to find potential drugs for cancer patients. Methods Colorectal cancer (CRC) patients were prospectively enrolled and blood samples were collected from patients before the start of treatment. Targeted deep sequencing of cfDNA samples was performed using a 14-gene panel. Gastrointestinal (GI) cancer organoids were established and PI3K and mTOR inhibitors were evaluated on organoid models. Results A total of 195 mutations were detected across 58 cfDNA samples. The most frequently mutated genes were KRAS, TP53, PIK3CA, and BRAF, all of which exhibited higher mutation rates than tissue biopsy. Although 81% of variants had an allele frequency of less than 1%, certain mutations in KRAS, TP53, and SMAD4 had high allele frequencies exceeding 10%. Notably, among the seven patients with high allele frequency mutations, six had metastatic tumors, indicating that a high allele frequency of ctDNA could potentially serve as a biomarker of later-stage cancer. A high rate of PIK3CA mutation (31 out of 67, or 46.3%) was discovered in CRC patients, suggesting possible tumor progression mechanisms and targeted therapy opportunities. To evaluate the value of anti PI3K strategy in GI cancer, different lines of GI cancer organoids were established. The organoids recapitulated the morphologies of the original tumors. Organoids were generally insensitive to PI3K inhibitors. However, CRC-3 and GC-4 showed response to mTOR inhibitor Everolimus, and GC-3 was sensitive to PI3Kδ inhibitor Idelalisib. The CRC organoid with a PIK3CA mutation showed greater sensitivity to the PI3K inhibitor Alpelisib than wildtype organoids, suggesting potential treatment options for the corresponding patients. Conclusion Liquid biopsy holds significant promise for improving precision treatment and tumor prognosis in colorectal cancer patients. The combination of biomarker-based drug prediction with organoid-based functional drug sensitivity assay may lead to more effective cancer treatment. |
| first_indexed | 2024-03-07T14:43:40Z |
| format | Article |
| id | doaj.art-6eca85a997db45e7b002c2affda436d3 |
| institution | Directory Open Access Journal |
| issn | 1479-5876 |
| language | English |
| last_indexed | 2024-03-07T14:43:40Z |
| publishDate | 2024-02-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Translational Medicine |
| spelling | doaj.art-6eca85a997db45e7b002c2affda436d32024-03-05T20:07:36ZengBMCJournal of Translational Medicine1479-58762024-02-0122111310.1186/s12967-023-04675-6Integrating cfDNA liquid biopsy and organoid-based drug screening reveals PI3K signaling as a promising therapeutic target in colorectal cancerHuan Yang0Xing Xiao1Leli Zeng2Haiteng Zeng3Yueyuan Zheng4Jingshu Wang5Guanghua Li6Weigang Dai7Yulong He8Suihai Wang9Jianjun Peng10Wei Chen11Department of Gastrointestinal Surgery, The First Affiliated Hospital of Sun Yat-Sen UniversityGuangdong Provincial Key Laboratory of Digestive Cancer ResearchDepartment of Biobank, The Seventh Affiliated Hospital of Sun Yat-Sen UniversityGuangdong Provincial Key Laboratory of Digestive Cancer ResearchClinical Big Data Research Center, Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen UniversityDepartment of Oncology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen UniversityDepartment of Gastrointestinal Surgery, The First Affiliated Hospital of Sun Yat-Sen UniversityDepartment of Gastrointestinal Surgery, The First Affiliated Hospital of Sun Yat-Sen UniversityGuangdong Provincial Key Laboratory of Digestive Cancer ResearchSchool of Laboratory Medicine and Biotechnology, Southern Medical UniversityDepartment of Gastrointestinal Surgery, The First Affiliated Hospital of Sun Yat-Sen UniversityGuangdong Provincial Key Laboratory of Digestive Cancer ResearchAbstract Background The current precision medicine relies on biomarkers, which are mainly obtained through next-generation sequencing (NGS). However, this model failed to find effective drugs for most cancer patients. This study tried to combine liquid biopsy with functional drug tests using organoid models to find potential drugs for cancer patients. Methods Colorectal cancer (CRC) patients were prospectively enrolled and blood samples were collected from patients before the start of treatment. Targeted deep sequencing of cfDNA samples was performed using a 14-gene panel. Gastrointestinal (GI) cancer organoids were established and PI3K and mTOR inhibitors were evaluated on organoid models. Results A total of 195 mutations were detected across 58 cfDNA samples. The most frequently mutated genes were KRAS, TP53, PIK3CA, and BRAF, all of which exhibited higher mutation rates than tissue biopsy. Although 81% of variants had an allele frequency of less than 1%, certain mutations in KRAS, TP53, and SMAD4 had high allele frequencies exceeding 10%. Notably, among the seven patients with high allele frequency mutations, six had metastatic tumors, indicating that a high allele frequency of ctDNA could potentially serve as a biomarker of later-stage cancer. A high rate of PIK3CA mutation (31 out of 67, or 46.3%) was discovered in CRC patients, suggesting possible tumor progression mechanisms and targeted therapy opportunities. To evaluate the value of anti PI3K strategy in GI cancer, different lines of GI cancer organoids were established. The organoids recapitulated the morphologies of the original tumors. Organoids were generally insensitive to PI3K inhibitors. However, CRC-3 and GC-4 showed response to mTOR inhibitor Everolimus, and GC-3 was sensitive to PI3Kδ inhibitor Idelalisib. The CRC organoid with a PIK3CA mutation showed greater sensitivity to the PI3K inhibitor Alpelisib than wildtype organoids, suggesting potential treatment options for the corresponding patients. Conclusion Liquid biopsy holds significant promise for improving precision treatment and tumor prognosis in colorectal cancer patients. The combination of biomarker-based drug prediction with organoid-based functional drug sensitivity assay may lead to more effective cancer treatment.https://doi.org/10.1186/s12967-023-04675-6Liquid biopsycfDNAColorectal cancerOrganoidPIK3CAAlpelisib |
| spellingShingle | Huan Yang Xing Xiao Leli Zeng Haiteng Zeng Yueyuan Zheng Jingshu Wang Guanghua Li Weigang Dai Yulong He Suihai Wang Jianjun Peng Wei Chen Integrating cfDNA liquid biopsy and organoid-based drug screening reveals PI3K signaling as a promising therapeutic target in colorectal cancer Journal of Translational Medicine Liquid biopsy cfDNA Colorectal cancer Organoid PIK3CA Alpelisib |
| title | Integrating cfDNA liquid biopsy and organoid-based drug screening reveals PI3K signaling as a promising therapeutic target in colorectal cancer |
| title_full | Integrating cfDNA liquid biopsy and organoid-based drug screening reveals PI3K signaling as a promising therapeutic target in colorectal cancer |
| title_fullStr | Integrating cfDNA liquid biopsy and organoid-based drug screening reveals PI3K signaling as a promising therapeutic target in colorectal cancer |
| title_full_unstemmed | Integrating cfDNA liquid biopsy and organoid-based drug screening reveals PI3K signaling as a promising therapeutic target in colorectal cancer |
| title_short | Integrating cfDNA liquid biopsy and organoid-based drug screening reveals PI3K signaling as a promising therapeutic target in colorectal cancer |
| title_sort | integrating cfdna liquid biopsy and organoid based drug screening reveals pi3k signaling as a promising therapeutic target in colorectal cancer |
| topic | Liquid biopsy cfDNA Colorectal cancer Organoid PIK3CA Alpelisib |
| url | https://doi.org/10.1186/s12967-023-04675-6 |
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