The biological essence of synthetic lethality: Bringing new opportunities for cancer therapy

Ge, Meiyi; Luo, Jian; Wu, Yi; Shen, Guobo; Kuang, Xi

doi:10.1002/mog2.70

Cited by 3 publications

(2 citation statements)

References 312 publications

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“…The examples described above provide a mere hint of this expanding field; a detailed overview of the state of the art is outside the scope of this Perspective. We therefore suggest the recent review by Ge et al for a more comprehensive analysis. Nevertheless, it is worth emphasizing how careful consideration of tumor heterogeneity could overcome some of the difficulties that SL strategies have had regarding translation from cellular to in vivo models and, ultimately, patients .…”

Section: Expanding the Definition Of Sl To Contextual Slmentioning

confidence: 99%

New Horizons of Synthetic Lethality in Cancer: Current Development and Future Perspectives

Previtali,

Bagnolini,

Ciamarone

et al. 2024

J. Med. Chem.

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In recent years, synthetic lethality has been recognized as a solid paradigm for anticancer therapies. The discovery of a growing number of synthetic lethal targets has led to a significant expansion in the use of synthetic lethality, far beyond poly(ADPribose) polymerase inhibitors used to treat BRCA1/2-defective tumors. In particular, molecular targets within DNA damage response have provided a source of inhibitors that have rapidly reached clinical trials. This Perspective focuses on the most recent progress in synthetic lethal targets and their inhibitors, within and beyond the DNA damage response, describing their design and associated therapeutic strategies. We will conclude by discussing the current challenges and new opportunities for this promising field of research, to stimulate discussion in the medicinal chemistry community, allowing the investigation of synthetic lethality to reach its full potential.

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Section: Expanding the Definition Of Sl To Contextual Slmentioning

confidence: 99%

New Horizons of Synthetic Lethality in Cancer: Current Development and Future Perspectives

Previtali,

Bagnolini,

Ciamarone

et al. 2024

J. Med. Chem.

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“…Numerous studies have leveraged metabolic characteristics and reprogramming to comprehend cancer-specific metabolic networks, identify potential anticancer targets, and, thus, inhibit tumor growth or viability [ 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 ]. Many drug discovery strategies, as noted in studies [ 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 ], have employed cancer cell mortality as a metric to gauge the effectiveness of the identified targets. However, the drug development process poses significant challenges due to its high expenses and prolonged timelines.…”

Section: Introductionmentioning

confidence: 99%

Identification of Anticancer Enzymes and Biomarkers for Hepatocellular Carcinoma through Constraint-Based Modeling

Wang,

Zhang

2024

Molecules

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Hepatocellular carcinoma (HCC) results in the abnormal regulation of cellular metabolic pathways. Constraint-based modeling approaches can be utilized to dissect metabolic reprogramming, enabling the identification of biomarkers and anticancer targets for diagnosis and treatment. In this study, two genome-scale metabolic models (GSMMs) were reconstructed by employing RNA sequencing expression patterns of hepatocellular carcinoma (HCC) and their healthy counterparts. An anticancer target discovery (ACTD) framework was integrated with the two models to identify HCC targets for anticancer treatment. The ACTD framework encompassed four fuzzy objectives to assess both the suppression of cancer cell growth and the minimization of side effects during treatment. The composition of a nutrient may significantly affect target identification. Within the ACTD framework, ten distinct nutrient media were utilized to assess nutrient uptake for identifying potential anticancer enzymes. The findings revealed the successful identification of target enzymes within the cholesterol biosynthetic pathway using a cholesterol-free cell culture medium. Conversely, target enzymes in the cholesterol biosynthetic pathway were not identified when the nutrient uptake included a cholesterol component. Moreover, the enzymes PGS1 and CRL1 were detected in all ten nutrient media. Additionally, the ACTD framework comprises dual-group representations of target combinations, pairing a single-target enzyme with an additional nutrient uptake reaction. Additionally, the enzymes PGS1 and CRL1 were identified across the ten-nutrient media. Furthermore, the ACTD framework encompasses two-group representations of target combinations involving the pairing of a single-target enzyme with an additional nutrient uptake reaction. Computational analysis unveiled that cell viability for all dual-target combinations exceeded that of their respective single-target enzymes. Consequently, integrating a target enzyme while adjusting an additional exchange reaction could efficiently mitigate cell proliferation rates and ATP production in the treated cancer cells. Nevertheless, most dual-target combinations led to lower side effects in contrast to their single-target counterparts. Additionally, differential expression of metabolites between cancer cells and their healthy counterparts were assessed via parsimonious flux variability analysis employing the GSMMs to pinpoint potential biomarkers. The variabilities of the fluxes and metabolite flow rates in cancer and healthy cells were classified into seven categories. Accordingly, two secretions and thirteen uptakes (including eight essential amino acids and two conditionally essential amino acids) were identified as potential biomarkers. The findings of this study indicated that cancer cells exhibit a higher uptake of amino acids compared with their healthy counterparts.

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BRCA1 orchestrates the response to BI-2536 and its combination with alisertib in MYC-driven small cell lung cancer

Zhang,

Liu,

Hou

et al. 2024

Cell Death Dis

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PLK1 is currently at the forefront of mitotic research and has emerged as a potential target for small cell lung cancer (SCLC) therapy. However, the factors influencing the efficacy of PLK1 inhibitors remain unclear. Herein, BRCA1 was identified as a key factor affecting the response of SCLC cells to BI-2536. Targeting AURKA with alisertib, at a non-toxic concentration, reduced the BI-2536-induced accumulation of BRCA1 and RAD51, leading to DNA repair defects and mitotic cell death in SCLC cells. In vivo experiments confirmed that combining BI-2536 with alisertib impaired DNA repair capacity and significantly delayed tumor growth. Additionally, GSEA analysis and loss- and gain-of-function assays demonstrated that MYC/MYCN signaling is crucial for determining the sensitivity of SCLC cells to BI-2536 and its combination with alisertib. The study further revealed a positive correlation between RAD51 expression and PLK1/AURKA expression, and a negative correlation with the IC50 values of BI-2536. Manipulating RAD51 expression significantly influenced the efficacy of BI-2536 and restored the MYC/MYCN-induced enhancement of BI-2536 sensitivity in SCLC cells. Our findings indicate that the BRCA1 and MYC/MYCN-RAD51 axes govern the response of small cell lung cancer to BI-2536 and its combination with alisertib. This study propose the combined use of BI-2536 and alisertib as a novel therapeutic strategy for the treatment of SCLC patients with MYC/MYCN activation.

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The biological essence of synthetic lethality: Bringing new opportunities for cancer therapy

Cited by 3 publications

References 312 publications

New Horizons of Synthetic Lethality in Cancer: Current Development and Future Perspectives

New Horizons of Synthetic Lethality in Cancer: Current Development and Future Perspectives

Identification of Anticancer Enzymes and Biomarkers for Hepatocellular Carcinoma through Constraint-Based Modeling

BRCA1 orchestrates the response to BI-2536 and its combination with alisertib in MYC-driven small cell lung cancer

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