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Published on: November 22, 2021
Targeting cancer drug resistance utilizing organoid technology
Changpeng Chai1, Pengfei Ji2, Hao Xu3
1The First Hospital of Lanzhou University, Lanzhou University, Lanzhou 730000, Gansu, China; The Forth Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou 730000, Gansu, China.
Abstract:
Cancer organoids generated from 3D in vitro cell cultures have contributed to the study of drug resistance. Maintenance of genomic and transcriptomic similarity between organoids and parental cancer allows organoids to have the ability of accurate prediction in drug resistance testing. Protocols of establishing therapy-sensitive and therapy-resistant organoids are concluded in two aspects, which are generated directly from respective patients' cancer and by induction of anti-cancer drug. Genomic and transcriptomic analyses and gene editing have been applied to organoid studies to identify key targets in drug resistance and FGFR3, KHDRBS3, lnc-RP11-536 K7.3 and FBN1 were found to be key targets. Furthermore, mechanisms contributing to resistance have been identified, including metabolic adaptation, activation of DNA damage response, defects in apoptosis, reduced cellular senescence, cellular plasticity, subpopulation interactions and gene fusions. Additionally, cancer stem cells (CSCs) have been verified to be involved in drug resistance utilizing organoid technology. Reversal of drug resistance can be achieved by targeting key genes and CSCs in cancer organoids. In this review, we summarize applications of organoids to cancer drug resistance research, indicating prospects and limitations.
Insights
Cancer organoids, 3D cell cultures, accurately predict drug resistance. Targeting key genes and cancer stem cells (CSCs) can reverse resistance, offering new therapeutic strategies.
Area of Science:
- Oncology
- Biotechnology
- Genomics
Background:
- Cancer organoids derived from 3D cell cultures are valuable tools for studying drug resistance.
- Maintaining genomic and transcriptomic similarity to parental tumors enables accurate prediction of drug resistance.
- Organoids can be established from patient tumors or induced to develop resistance through drug treatment.
Purpose of the Study:
- To review the applications of cancer organoids in understanding and overcoming drug resistance.
- To identify key molecular targets and mechanisms involved in cancer drug resistance.
- To discuss the potential and limitations of organoid technology in cancer research.
Main Methods:
- Genomic and transcriptomic analyses of organoids to identify resistance-associated genes.
- Gene editing techniques to validate the role of identified targets.
- Establishment of both therapy-sensitive and therapy-resistant organoid models.
Main Results:
- Key genes (FGFR3, KHDRBS3, lnc-RP11-536 K7.3, FBN1) implicated in drug resistance were identified.
- Mechanisms of resistance include metabolic adaptation, DNA damage response, apoptosis defects, reduced senescence, plasticity, subpopulation interactions, and gene fusions.
- Cancer stem cells (CSCs) were confirmed to play a role in drug resistance using organoid models.
Conclusions:
- Cancer organoids are effective models for studying drug resistance mechanisms.
- Targeting identified key genes and CSCs holds promise for reversing drug resistance.
- Organoid technology offers significant prospects but also presents limitations in cancer drug resistance research.
