Mutant RB1 enhances therapeutic efficacy of PARPis in lung adenocarcinoma by triggering the cGAS/STING pathway
Qi Dong, … , Yang Hui, Yunyan Gu
Qi Dong, … , Yang Hui, Yunyan Gu
Published November 8, 2023
Citation Information: JCI Insight. 2023;8(21):e165268. https://doi.org/10.1172/jci.insight.165268.
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Mutant RB1 enhances therapeutic efficacy of PARPis in lung adenocarcinoma by triggering the cGAS/STING pathway

Abstract

Poly (ADP-ribose) polymerase inhibitors (PARPis) are approved for cancer therapy according to their synthetic lethal interactions, and clinical trials have been applied in non–small cell lung cancer. However, the therapeutic efficacy of PARPis in lung adenocarcinoma (LUAD) is still unknown. We explored the effect of a mutated retinoblastoma gene (RB1) on PARPi sensitivity in LUAD. Bioinformatic screening was performed to identify PARPi-sensitive biomarkers. Here, we showed that viability of LUAD cell lines with mutated RB1 was significantly decreased by PARPis (niraparib, rucaparib, and olaparib). RB1 deficiency induced genomic instability, prompted cytosolic double-stranded DNA (dsDNA) formation, activated the cGAS/STING pathway, and upregulated downstream chemokines CCL5 and CXCL10, triggering immune cell infiltration. Xenograft experiments indicated that PARPi treatment reduced tumorigenesis in RB1-KO mice. Additionally, single-cell RNA sequencing analysis showed that malignant cells with downregulated expression of RB1 had more communications with other cell types, exhibiting activation of specific signaling such as GAS, IFN response, and antigen-presenting and cytokine activities. Our findings suggest that RB1 mutation mediates the sensitivity to PARPis through a synthetic lethal effect by triggering the cGAS/STING pathway and upregulation of immune infiltration in LUAD, which may be a potential therapeutic strategy.

Authors

Qi Dong, Tong Yu, Bo Chen, Mingyue Liu, Xiang Sun, Huiying Cao, Kaidong Liu, Huanhuan Xu, Yuquan Wang, Shuping Zhuang, Zixin Jin, Haihai Liang, Yang Hui, Yunyan Gu

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Figure 3

Loss-of-function mutations of RB1.

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Loss-of-function mutations of RB1. (A and B) Distribution of RB1 mRNA ex...
(A and B) Distribution of RB1 mRNA expression in cell lines with mutated RB1 and WT RB1 in TCGA, DepMap, and COSMIC data sets. (C–E) Distribution of RB1 protein expression in cell lines with mutated RB1 and WT RB1 in TCGA and DepMap data sets. (F) qRT-PCR analysis of RB1 levels in 3 RB1-WT LUAD cell lines (A549, H1650, and H1975) and 2 RB1-mutant LUAD cell lines (H2228 and H1781) (n = 6). *P < 0.05, **P < 0.01 vs. RB1-WT cells. (G) Western blot analysis of RB1 protein expression in RB1-WT and RB1-mutant LUAD cell lines (n = 5). *P < 0.05, **P < 0.01 vs. RB1-WT cells. (H and I) Distribution of ln(IC50) (LN_IC50) and AUC in RB1-WT and -mutant lung cancer cell lines treated with PARPis in the GDSC data set. (J and K) Distribution of ln(IC50) in RB1-H and RB1-L breast cancer cell lines treated with PARPis in the GDSC data set. (L) Distribution of RD and pCR patients with RB1-H and RB1-L in the GSE164458 data set. (M) Expression of RB1 between RD and pCR patients in the GSE164458 data set. P values were calculated by 1-sided Wilcoxon’s rank-sum test (A–E, H–K, and M), unpaired, 2-tailed Student’s t test (F and G), and hypergeometric test (L).