Article
Biochemistry & Molecular Biology
Siddhant Bhoir, Oluwatobi Ogundepo, Xiuping Yu, Runhua Shi, Arrigo De Benedetti
Summary: This study discovers that enhancing the therapeutic effect of cisplatin (CPT) on androgen-insensitive prostate cancer cells can be achieved by inhibiting TLK1 protein. TLK1, through phosphorylation of RAD54L and RAD54B proteins, participates in homologous recombination repair (HRR) and interferes with the HRR process, thus increasing sensitivity to CPT.
Review
Biochemistry & Molecular Biology
Parasvi S. Patel, Arash Algouneh, Razq Hakem
Summary: The principle of synthetic lethality, aiming at disrupting two genes to eliminate tumors, particularly in BRCA1/2-mutated cancers, has been a focus in cancer research. Although PARP inhibitors have shown clinical success in certain cases, resistance remains an issue and the exploration of alternative targets is crucial for future therapies. Various synthetic lethal interactors of BRCA1/2 have been identified, providing potential avenues for the development of new targeted therapies.
Article
Multidisciplinary Sciences
Biyu Zhang, Chen Tang, Yanli Yao, Xiaohan Chen, Chi Zhou, Zhiting Wei, Feiyang Xing, Lan Chen, Xiang Cai, Zhiyuan Zhang, Shuyang Sun, Qi Liu
Summary: Synthetic lethality is becoming an important cancer therapeutic paradigm, but comprehensive selective treatment opportunities for various tumors have not been fully explored. The Synthetic Lethality Knowledge Graph (SLKG) integrates data on different tumors, drugs, and drug targets to provide therapy options for synthetic lethality and synthetic dosage lethality, prioritizing the identification of repurposable drug candidates and combinations with supporting evidence for novel tumor therapy discovery.
NATURE COMMUNICATIONS
(2021)
Review
Oncology
Liliana Raimundo, Juliana Calheiros, Lucilia Saraiva
Summary: Chemical inhibition of central DDR proteins, especially BRCA1, has become a promising approach in precision cancer therapy. PARPi, as a targeted therapy, exploits cancer cells' inability to repair DNA damage. However, drug resistance and the search for additional agents targeting DDR remain crucial for advancing precision cancer medicine.
Review
Oncology
Laia Castells-Roca, Eudald Tejero, Benjamin Rodriguez-Santiago, Jordi Surralles
Summary: The concept of synthetic lethality (SL) has played a crucial role in cancer treatment, with CRISPR technology being widely used to discover new genetic interactions. Combining therapies based on SL interactions have the potential to reduce toxicity and improve efficacy in cancer treatment.
Article
Pharmacology & Pharmacy
Hua-Li Wang, Xue Ma, Xin-Yuan Guan, Chen Song, Guo-Bo Li, Ya-Mei Yu, Ling-Ling Yang
Summary: This study found that a highly selective SIRT2 inhibitor, I, combined with sorafenib showed significant synergistic reduction in cell viability of MCF-7 cells. The combination treatment suppressed cell proliferation, migration, arrested cell cycle at G0/G1 phase, and induced apoptosis in MCF-7 cells. In vivo experiments also showed that the combination treatment had stronger tumor growth inhibition compared to single treatments with I or sorafenib alone.
PHARMACOLOGICAL RESEARCH
(2022)
Review
Pharmacology & Pharmacy
Zekun Zeng, Wenfang Zheng, Peng Hou
Summary: Drug-metabolizing enzymes (DMEs) play an important role in anticancer therapy, not only influencing the action of anticancer drugs, but also being closely associated with pathological and biochemical changes during tumor progression. Synthetic lethal strategy, using unique genetic markers to discover selectively targeted anticancer drugs for cancer cells, has become more accessible. Dysregulation of DMEs has been found in various cancers, making them potential candidates for synthetic lethal strategy.
PHARMACOLOGY & THERAPEUTICS
(2022)
Review
Immunology
Amr Allam, Marina Yakou, Lokman Pang, Matthias Ernst, Jennifer Huynh
Summary: This article discusses the relationship between cancer-associated fibroblasts (CAFs) and signal transducer and activator of transcription 3 (STAT3) in the tumor microenvironment, as well as their impact on tumor growth, immune suppression, and metastatic spread. Research suggests that CAF-intrinsic STAT3 activity is closely associated with tumor progression.
FRONTIERS IN IMMUNOLOGY
(2021)
Review
Oncology
Shuangying Li, Liangliang Wang, Yuanyuan Wang, Changyi Zhang, Zhenya Hong, Zhiqiang Han
Summary: Continuous cell division is a characteristic of cancer, and cell cycle checkpoints play a critical role in maintaining genome stability during cell division. DNA damage checkpoints primarily monitor genetic errors and facilitate DNA repair, while DNA replication stress checkpoints protect against replication catastrophe and maintain genome integrity. A combination therapy targeting cell cycle checkpoints and PARP inhibitors can increase the death rate of cancer cells with DNA repair deficiency or PARP inhibitor resistance by increasing DNA errors and compromising the DNA repair machinery.
JOURNAL OF HEMATOLOGY & ONCOLOGY
(2022)
Article
Medicine, Research & Experimental
Chen Yang, Yuchen Guo, Ruolan Qian, Yiwen Huang, Linmeng Zhang, Jun Wang, Xiaowen Huang, Zhicheng Liu, Wenxin Qin, Cun Wang, Huimin Chen, Xuhui Ma, Dayong Zhang
Summary: Through the analysis of synthetic lethality interactions, potential therapeutic targets in liver cancer were identified, suggesting a novel personalized treatment approach. This may offer more effective treatment options for patients with liver cancer.
Review
Oncology
Yucui Xin, Yingsheng Zhang
Summary: Tumor cells can be specifically targeted by disrupting the function of the other genes in synthetic lethality (SL) settings, while leaving normal cells unharmed. Paralogs, homologous genes that have diverged from each other, are ideal SL targets in tumor cells due to their frequent homozygous loss. However, the unclear mechanisms of targeting these gene pairs and the difficulty in finding specific inhibitors hinder further clinical development.
FRONTIERS IN ONCOLOGY
(2023)
Review
Oncology
Erik H. Knelson, Shetal A. Patel, Jacob M. Sands
Summary: Small-cell lung cancer has a poor prognosis with limited treatment options. PARP inhibitors have shown promise as a therapeutic target, especially when used in combination therapies that contribute to DNA damage, inhibit the DNA damage response, or activate the immune system. Identifying biomarkers and developing treatment combinations based on the evolving classification of small-cell lung cancer subtypes and gene expression patterns will be crucial for improving outcomes in this challenging cancer.
Review
Biochemistry & Molecular Biology
Hannah E. Neiger, Emily L. Siegler, Yihui Shi
Summary: BRCA1 and BRCA2 are tumor suppressor genes crucial in DNA repair mechanisms. Synthetic lethality, caused by simultaneous perturbations of two genes, can help identify new therapeutic options for BRCA1/2 mutations. PARP inhibitor Olaparib has shown success as the first synthetic lethality-based therapy for BRCA1/2 breast and ovarian cancer, but drug resistance poses a challenge for targeted cancer therapy.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Oncology
Federica Invrea, Simona Punzi, Consalvo Petti, Rosalba Minelli, Michael D. Peoples, Christopher A. Bristow, Valentina Vurchio, Alessia Corrado, Alberto Bragoni, Caterina Marchio, Andrea Bertotti, Livio Trusolino, Alberto Bardelli, Claudio Isella, Alessandro Carugo, Giulio F. Draetta, Enzo Medico
Summary: This study identified a promising therapeutic strategy for clinically aggressive CRC resistant to EGFR and BRAF-targeted treatments by combining the NEDD8 pathway inhibitor pevonedistat with EGFR pathway-targeted treatments, reversing compensatory feedback loops and inhibiting tumor growth and inducing apoptosis in preclinical models.
Article
Oncology
Caiyu Sun, Weiqiang Jing, Gaozhong Xiong, Dapeng Ma, Yueke Lin, Xiaoting Lv, Yunxue Zhao, Xiaomin Ma, Lihui Zhu, Xuecheng Shen, Min Yang, Zhenzhi Qin, Yeping Cheng, Haocheng Xuan, Tao Li, Lihui Han
Summary: This study identified Src and PARP1 as novel synthetic lethal partners, and the combination therapy showed significant anti-tumor effects without causing obvious side effects. The findings suggest that targeting both PARP1 and Src may broaden the strategies for HCC treatment and benefit patients with high Src activation and resistance to PARP1 inhibitors alone.
