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Systematic identification of cancer-type-specific drugs based on essential genes and validations in lung
Xiang Lian1,2, Xia Kuang1, Dong-Dong Zhang1
1Department of Respiratory and Critical Care Medicine, Zhongnan Hospital of Wuhan University, School of Pharmaceutical Sciences, Wuhan University, 185 Donghu Road, Wuchang District, Wuhan 430071, China.
Abstract:
Depicting a global landscape of essential gene-targeting drugs would provide more opportunities for cancer therapy. However, a systematic investigation on drugs targeting essential genes still has not been reported. We suppose that drugs targeting cancer-type-specific essential genes would generally have less toxicity than those targeting pan-cancer essential genes. A scoring function-based strategy was developed to identify cancer-type-specific targets and drugs. The EssentialitySpecificityScore ranked the essential genes in 19 cancer types, and 1151 top genes were identified as cancer-type-specific targets. Combining target-drug interaction databases with research/marketing status, 370 cancer-type-specific drugs were identified, bound to 100 out of all identified targets. Profiles of applied cancer types of identified targets and drugs illustrate the scoring strategy's effectiveness: most drugs apply to cancer types <10. Seven drugs with no previous anticancer evidence were validated in 11 lung adenocarcinoma cell lines, and lower inhibition rates (from 9.4% to 44.0%) were observed in 10 normal cell lines. This difference is statistically significant (Student's t-test, P ≤ .0001), confirming the rationality of our supposition. Our built EGKG (Essential Gene Knowledge Graph) forms a computational basis to uncover essential gene targets and drugs for specific cancer types. It is available at http://gepa.org.cn/egkg/. Also, our experimental result suggests that combining drugs with orthogonal essentiality may be an alternative way to improve anticancer effects while maintaining biocompatibility. The code and data are available at https://github.com/KKINGA1/EGKG_data_process.
Insights
Researchers identified cancer-type-specific essential genes and drugs, showing lower toxicity compared to pan-cancer targets. This discovery offers new avenues for targeted cancer therapy with improved biocompatibility.
Area of Science:
- Oncology
- Pharmacology
- Bioinformatics
Background:
- Targeting essential genes is crucial for cancer therapy, but systematic investigations are lacking.
- Existing drugs targeting essential genes may exhibit broad toxicity, necessitating more specific approaches.
Purpose of the Study:
- To develop a strategy for identifying cancer-type-specific essential gene targets and associated drugs.
- To evaluate the potential for reduced toxicity of drugs targeting cancer-specific essential genes compared to pan-cancer targets.
Main Methods:
- A scoring function (EssentialitySpecificityScore) was developed to rank essential genes across 19 cancer types.
- Cancer-type-specific targets and drugs were identified by integrating gene essentiality data with drug interaction databases and market status.
- Experimental validation was performed on selected drugs in lung adenocarcinoma cell lines.
Main Results:
- 1151 cancer-type-specific essential genes and 370 drugs targeting 100 of these genes were identified.
- Drugs associated with cancer-type-specific targets were found to apply to fewer cancer types (<10).
- Seven novel drugs showed significantly lower inhibition rates in normal cell lines compared to cancer cell lines (P ≤ 0.0001).
Conclusions:
- The developed scoring strategy effectively identifies cancer-type-specific targets and drugs, supporting the hypothesis of reduced toxicity.
- The Essential Gene Knowledge Graph (EGKG) provides a computational framework for discovering targeted cancer therapies.
- Combining drugs with orthogonal essentiality may enhance anticancer efficacy while preserving biocompatibility.
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