GLI1 confers resistance to PARP inhibitors by activating the DNA damage repair pathway

• Published in: Oncogene 2024-10, Vol.43 (41), p.3037-3048
• Main Authors: Ikeuchi, Hiroshi, Matsuno, Yusuke, Kusumoto-Matsuo, Rika, Kojima, Shinya, Ueno, Toshihide, Ikegami, Masachika, Kitada, Rina, Sumiyoshi-Okuma, Hitomi, Kojima, Yuki, Yonemori, Kan, Yatabe, Yasushi, Takamochi, Kazuya, Suzuki, Kenji, Yoshioka, Ken-ichi, Mano, Hiroyuki, Kohsaka, Shinji
• Format: Article
• Language: English
• Subjects: 13/95; 45/44; 45/91; 631/67/1857; 631/67/395; 631/67/69; Animals; Antineoplastic drugs; Apoptosis; BRCA1 protein; BRCA2 protein; Cell Biology; Cell Line, Tumor; DNA damage; DNA Damage - drug effects; DNA repair; DNA Repair - drug effects; DNA Repair - genetics; Drug development; Drug efficacy; Drug resistance; Drug Resistance, Neoplasm - genetics; Drug screening; Female; Gene set enrichment analysis; Genetic diversity; Homologous recombination; Homologous recombination repair; Human Genetics; Humans; Internal Medicine; Medicine; Medicine & Public Health; Mice; Nucleotide excision repair; Oncology; Phthalazines - pharmacology; Piperazines - pharmacology; Poly(ADP-ribose) polymerase; Poly(ADP-ribose) Polymerase Inhibitors - pharmacology; Targeted cancer therapy; Xenograft Model Antitumor Assays; Zinc Finger Protein GLI1 - genetics; Zinc Finger Protein GLI1 - metabolism
• ISSN: 0950-9232; 1476-5594; 1476-5594
• DOI: 10.1038/s41388-024-03105-1

Identifying the mechanisms of action of anticancer drugs is an important step in the development of new drugs. In this study, we established a comprehensive screening platform consisting of 68 oncogenes (MANO panel), encompassing 243 genetic variants, to identify predictive markers for drug efficacy. Validation was performed using drugs that targeted EGFR, BRAF, and MAP2K1, which confirmed the utility of this functional screening panel. Screening of a BRCA2 -knockout DLD1 cell line (DLD1-KO) revealed that cells expressing SMO and GLI1 were resistant to olaparib. Gene set enrichment analysis identified genes associated with DNA damage repair that were enriched in cells overexpressing SMO and GLI1 . The expression of genes associated with homologous recombination repair (HR), such as the FANC family and BRCA1/2 , was significantly upregulated by GLI1 expression, which is indicative of PARP inhibitor resistance. Although not all representative genes of the nucleotide excision repair (NER) pathway were upregulated, NER activity was enhanced by GLI1 . The GLI1 inhibitor was effective against DLD1-KO cells overexpressing GLI1 both in vitro and in vivo. Furthermore, the combination therapy of olaparib and GLI1 inhibitor exhibited a synergistic effect on DLD1-KO, suggesting the possible clinical application of GLI1 inhibitor targeting cancer with defective DNA damage repair. This platform enables the identification of biomarkers associated with drug sensitivity, and is a useful tool for drug development.