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

Autor: Ikeuchi H; Division of Cellular Signaling, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan.; Department of General Thoracic Surgery, Juntendo University School of Medicine, Tokyo, Japan., Matsuno Y; Laboratory of Genome Stability Maintenance, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan., Kusumoto-Matsuo R; Laboratory of Genome Stability Maintenance, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan., Kojima S; Division of Cellular Signaling, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan., Ueno T; Division of Cellular Signaling, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan., Ikegami M; Division of Cellular Signaling, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan.; Department of Musculoskeletal Oncology, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, Japan., Kitada R; Division of Cellular Signaling, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan., Sumiyoshi-Okuma H; Department of Medical Oncology, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan., Kojima Y; Department of Medical Oncology, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan., Yonemori K; Department of Medical Oncology, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan., Yatabe Y; Department of Diagnostic Pathology, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan., Takamochi K; Department of General Thoracic Surgery, Juntendo University School of Medicine, Tokyo, Japan., Suzuki K; Department of General Thoracic Surgery, Juntendo University School of Medicine, Tokyo, Japan., Yoshioka KI; Laboratory of Genome Stability Maintenance, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan., Mano H; Division of Cellular Signaling, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan., Kohsaka S; Division of Cellular Signaling, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan. skohsaka@ncc.go.jp.
Jazyk: angličtina
Zdroj: Oncogene [Oncogene] 2024 Oct; Vol. 43 (41), pp. 3037-3048. Date of Electronic Publication: 2024 Aug 03.
DOI: 10.1038/s41388-024-03105-1
Abstrakt: 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.
(© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)
Databáze: MEDLINE
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