Targeting cancer drug resistance utilizing organoid technology

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, lncRP11-536 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.

Automated summary

Cancer organoids generated from 3D in vitro cell cultures have provided valuable insights into drug resistance mechanisms. These organoids accurately predict drug resistance due to their genomic and transcriptomic similarity to parental cancer cells. Methods for establishing therapy-sensitive and therapy-resistant organoids involve either direct culture from patient samples or induction with anti-cancer drugs. Genomic and transcriptomic analyses and gene editing have identified key targets in drug resistance, including FGFR3, KHDRBS3, lncRP11-536 K7.3, and FBN1. Mechanisms contributing to resistance include metabolic adaptation, DNA damage response activation, apoptosis defects, reduced cellular senescence, cellular plasticity, subpopulation interactions, and gene fusions. Cancer stem cells (CSCs) have also been implicated in drug resistance using organoid technology. Targeting key genes and CSCs in cancer organoids can reverse drug resistance. This review summarizes the applications of organoids in cancer drug resistance research, highlighting their prospects and limitations.