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Role of ALDH1A1 in PARPi resistance in ovarian cancer

ABSTRACT: Poly (ADP-ribose) Polymerase (PARP) inhibitors (PARPi) are approved to treat recurrent ovarian cancer with BRCA1 or BRCA2 mutations, and as maintenance therapy for recurrent platinum sensitive ovarian cancer (BRCA wild-type or mutated) after treatment with platinum. However, the acquired resistance against PARPi remains a clinical hurdle. Our previous study has demonstrated that PARPi can enhance the Aldehyde dehydrogenase (ALDH) activity in ovarian cancer cells, mainly through inducing expression of ALDH1A1, an isoform of the ALDH family. In addition, an ALDH1A1 selective inhibitor can synergize with olaparib in killing EOC cells carrying BRCA2 mutation in both in vitro cell culture and the in vivo xenograft animal model. In order to elucidating the mechanism by which ALDH1A1 renders PARPi resistance to ovarian cancer, we performed RNA-seq analysis to identify genes whose expression can be regulated by ALDH1A1.

ORGANISM(S): Homo sapiens

PROVIDER: GSE226018 | GEO | 2023/07/19

REPOSITORIES: GEO

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Project description:Extending the therapeutic spectrum of PARP-inhibition (PARPi) beyond HR-deficiency or reverting PARPi resistance is of high clinical interest. This is particularly true for the identification of innovative therapeutic strategies for ovarian cancer, given the recent advances in the use of PARPi in clinical practice. In this regard, the combination of PARPi with chemotherapy is a promising strategy for defining new therapeutic standards. In this study, we analysed the therapeutic effect of novel triazene derivatives, including the drug CT913 and its metabolite CT913-M1 on ovarian cancer cells and describe their interaction with PARPi. This is the first study analysing the potential therapeutic effect of these components. In vitro assays for drug characterization including RNA-seq were applied in a selected panel of ovarian cancer cell lines. CT913 treatment conferred a dose-dependent reduction of cell viability in a set of platinum-sensitive and platinum-resistant ovarian cancer cell lines with an IC50 in the micro- to almost millimolar range (107-940µM), whereas its metabolite CT913-M1 was about 10-fold more potent (IC50 of 17-93µM). Neither of the drugs increased the cytotoxic effect of cisplatin, CT913 might even antagonize it. Furthermore, CT913 conferred synthetic lethality in BRCA1-deficient ovarian cancer cells, indicating that homologues recombination (HR) repair may contribute to its mechanism of action. Importantly, CT913 sensitized for olaparib treatment, independently of BRCA-1 mutational status, supporting the finding that CT913 may act partially independent of an impaired HR. CT913 treatment led to changes in gene transcription. CT913 strongly induced CDKN1A transcription, suggesting cell cycle arrest as an early response to this drug. It also downregulated a variety of transcripts involved in prominent DNA-repair pathways, such as HR, mismatch repair (MMR) or nucleotide excision repair (NER). This is the first study, suggesting the triazene drug class CT913 as auxiliary drug for extending the therapeutic spectrum of PARPi.

Project description:Background: Liver transplantation (LT) for Hepatocellular carcinoma (HCC) can be offered to patients beyond Milan criteria. However, there are currently no molecular markers that can be used on HCC explant histology to predict recurrence, which arises in up to 20% of LT recipients. The goal of our study was to identify proteins on HCC explant predictive of recurrence post-transplant, thereby guiding surveillance strategies and identifying patients beyond Milan criteria who would fare well following LT. Methods: LT recipients who had been transplanted at the University Health Network for HCC beyond Milan criteria in the context of Hepatitis B cirrhosis were identified. Snap-frozen samples from the dominant tumors of recurrent (N=7) and non-recurrent (N=4) patients were analyzed using LC-MS/MS on a Q-Exactive Plus mass spectrometer to delineate a distinctive proteomic signature. These tumors were also profiled by a Human Gene 2.0 ST microarray platform to identify a transcriptomic signature predictive of recurrence and analyzed with R packages. STRING database was used to characterize the implicated pathways. Kaplan-Meier estimator was used to generate a combined proteomic/transcriptomic signature predictive of HCC recurrence in patients with HCC beyond Milan criteria at time of LT. Significantly predictive proteins were verified and internally validated by immunoblotting or immunohistochemistry. Results: A total of 79 proteins and 636 genes were significantly differentially expressed in recurrent HCC, compared to non-recurrent (p<0.05). Among these, LGALS3, LGALS3BP, HAL, THBS1, and BLMH, were significantly increased in recurrent HCC at the protein and gene expression level. In turn, ALDH1A1 protein and gene expression were significantly decreased in recurrent HCC. Univariate survival analysis depicted ALDH1A1 (HR=0.084, 95%CI 0.01-0.68, p=0.02), LGALS3BP (HR=7.14, 95%CI 1.20-42.96, p=0.03), and LGALS3 (HR=2.89, 95%CI 1.01-8.3, p=0.049) as the key dysregulated proteins and genes in the patients with HCC recurrence versus those with non-recurrence by both proteomic and transcriptomic analysis. Decreased ALDH1A1 and significantly increased LGALS3 protein expression in recurrent HCC was verified by immunoblotting. Increased LGALS3BP protein expression in recurrent HCC was orthogonally verified and validated by immunohistochemistry in 30 independent HCC samples. Conclusion: Protein and gene expression of the cancer stem cell marker ALDH1A1 was protective against cancer recurrence in patients transplanted for HCC beyond Milan criteria. Conversely, increased expression of LGALS3 and LGALS3BP on explant was significantly predictive of post-transplant recurrence. These findings were internally validated, suggesting potential utility in identifying patients with HCC beyond Milan who would clearly benefit from transplant with limited recurrence risk and guiding post-transplant surveillance.

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Role of ALDH1A1 in PARPi resistance in ovarian cancer

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