Combining targeted DNA repair inhibition and immune-oncology approaches for enhanced tumor control

Concannon, Kyle; Morris, Benjamin B.; Gay, Carl M.; Byers, Lauren A.

doi:10.1016/j.molcel.2022.12.031

Cited by 17 publications

(8 citation statements)

References 164 publications

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“…For instance, BRCA1 promoter methylation or other potential mutations in DDR genes can lead to BRCA1 /2 deficiency in patients with breast cancer ( 41 ). The combination therapy of cisplatin and PD-1 significantly enhanced the anti-tumor immunity of BRCA1 -deficient mice, resulting in a strong systemic and intratumoral immune response ( 42 ). Furthermore, triple-negative breast cancer (TNBC) with BRCA1 mutations treated with ICB therapy was reported to improved clinical outcomes.…”

Section: Discussionmentioning

confidence: 99%

Prognostic analysis of patients with breast cancer based on tumor mutational burden and DNA damage repair genes

Teng,

Yang,

Yuan

et al. 2023

Front. Oncol.

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BackgroundBreast cancer has a high tumor-specific death rate and poor prognosis. In this study, we aimed to provide a basis for the prognostic risk in patients with breast cancer using significant gene sets selected by analyzing tumor mutational burden (TMB) and DNA damage repair (DDR).MethodsBreast cancer genomic and transcriptomic data were obtained from The Cancer Genome Atlas (TCGA). Breast cancer samples were dichotomized into high- and low-TMB groups according to TMB values. Differentially expressed DDR genes between high- and low-TMB groups were incorporated into univariate and multivariate cox regression model to build prognosis model. Performance of the prognosis model was validated in an independently new GEO dataset and evaluated by time-dependent ROC curves.ResultsBetween high- and low-TMB groups, there were 6,424 differentially expressed genes, including 67 DDR genes. Ten genes associated with prognosis were selected by univariate cox regression analysis, among which seven genes constituted a panel to predict breast cancer prognosis. The seven-gene prognostic model, as well as the gene copy numbers are closely associated with tumor-infiltrating immune cells.ConclusionWe established a seven-gene prognostic model comprising MDC1, PARP3, PSMB1, PSMB9, PSMD2, PSMD7, and PSMD14 genes, which provides a basis for further exploration of a population-based prediction of prognosis and immunotherapy response in patients with breast cancer.

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Section: Discussionmentioning

confidence: 99%

Prognostic analysis of patients with breast cancer based on tumor mutational burden and DNA damage repair genes

Teng,

Yang,

Yuan

et al. 2023

Front. Oncol.

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“…In addition, the inability of MS023 treated cells to repair DSBs suggests the possibility of synergy with other DNA repair targeted drugs such as PARP inhibitors. Finally, the induction of DNA damage may lead to increased neoantigen load and/or stimulate the cGAS/STING pathway 52 , leading to increased sensitivity to immune checkpoint blockade. Further studies are needed to investigate these possibilities.…”

Section: Discussionmentioning

confidence: 99%

PRMT1 is a critical dependency in clear cell renal cell carcinoma through its role in post-transcriptional regulation of DNA damage response genes

Walton

Arevalo

et al. 2023

Preprint

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Biallelic inactivation of the Von Hippel-Lindau (VHL) tumor suppressor gene occurs in almost all cases of clear cell renal cell carcinoma (ccRCC) and leads to disrupted oxygen sensing and the upregulation of hypoxia-related genetic programs. Although the loss of VHL appears to be a necessary oncogenic driver event in the majority of ccRCC instances, it is not always a sufficient one. Large genomics studies have revealed that co-deletions of VHL with genes involved in chromatin regulation are common and important co-drivers of tumorigenesis. Several conserved evolutionary subtypes have been described clinically and the majority implicate disruptions in epigenetic regulators. It is now clear that impairments in cellular epigenetic mechanisms are important co-drivers of disease and signal a potential vulnerability in the epigenetic network of ccRCC cells relative to their normal counterparts. Using a clinically relevant panel of ccRCC models, we herein sought to exploit this potential vulnerability by screening a library of small molecule inhibitors that target a spectrum of epigenetic regulators. We identified MS023, an inhibitor of type I protein arginine methyltransferases (PRMTs) as an agent with antitumor activity. Using orthogonal genetic technologies, we further validated PRMT1 as the specific critical dependency for cancer growth. Mechanistically, our transcriptomic and functional analyses suggest that MS023 treatment results in substantial impairments to cell cycle and DNA damage repair (DDR) pathways, while spawning an accumulation of DNA damage over time. Our PRMT1 specific proteomics analysis revealed an interactome rich in RNA binding proteins including the specific regulator of DDR mRNA metabolism: the BCLAF1/THRAP3 complex. Further investigation suggests that MS023 treatment may result in impairments to DDR specific mRNA activities including nucleocytoplasmic transport and RNA splicing. Together, our data supports PRMT1 as a compelling target in ccRCC and informs a potential mechanism-based strategy for translational development.

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“…Early success in these trials underscores the importance of promoting anti-tumor immune responses, which are primed in DNA damage settings. Further discussion of the potential molecular mechanisms and immune pathways can be found in additional reviews ( Concannon et al, 2023 ).…”

Section: Parpi and Immunotherapymentioning

confidence: 99%

Targeting the BRCA1/2 deficient cancer with PARP inhibitors: Clinical outcomes and mechanistic insights

Ragupathi

Singh

Perez

et al. 2023

Front. Cell Dev. Biol.

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BRCA1 and BRCA2 play a critical role in a variety of molecular processes related to DNA metabolism, including homologous recombination and mediating the replication stress response. Individuals with mutations in the BRCA1 and BRCA2 (BRCA1/2) genes have a significantly higher risk of developing various types of cancers, especially cancers of the breast, ovary, pancreas, and prostate. Currently, the Food and Drug Administration (FDA) has approved four PARP inhibitors (PARPi) to treat cancers with BRCA1/2 mutations. In this review, we will first summarize the clinical outcomes of the four FDA-approved PARPi in treating BRCA1/2 deficient cancers. We will then discuss evidence supporting the hypothesis that the cytotoxic effect of PARPi is likely due to inducing excessive replication stress at the difficult-to-replicate (DTR) genomic regions in BRCA1/2 mutated tumors. Finally, we will discuss the ongoing preclinical and clinical studies on how to combine the PARPi with immuno-oncology drugs to further improve clinical outcomes.

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Combining targeted DNA repair inhibition and immune-oncology approaches for enhanced tumor control

Cited by 17 publications

References 164 publications

Prognostic analysis of patients with breast cancer based on tumor mutational burden and DNA damage repair genes

Prognostic analysis of patients with breast cancer based on tumor mutational burden and DNA damage repair genes

PRMT1 is a critical dependency in clear cell renal cell carcinoma through its role in post-transcriptional regulation of DNA damage response genes

Targeting the BRCA1/2 deficient cancer with PARP inhibitors: Clinical outcomes and mechanistic insights

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