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A combination therapy for KRAS-mutant lung cancer by targeting synthetic lethal partners of mutant KRAS

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Chinese Journal of Cancer 2016年第11期35卷 571-573页

作者： Xiufeng Pang Mingyao Liu Shanghai Key Laboratory of Regulatory Biology Institute of Biomedical Sciences and School of Life SciencesEast China Normal University Department of Molecular and Cellular Medicine Institute of Biosciences and TechnologyTexas A&M University Health Science Center

The KRAS gene is frequently mutated in multiple cancer types,but it fell off the drug discovery radar for many years because of its inherent "undruggable" structure and undefined biological *** reported in the paper entitled "Suppression of KRas-mutant cancer through the combined inhibition of KRAS with PLK1 and ROCK" in Nature Communications,we performed a synthetic lethal screening with a combinatorial strategy on a panel of clinical drugs;we found that combined inhibition of polo-like kinase 1 and RhoA/Rho kinase markedly suppressed tumor growth in *** increase in the expression of the tumor suppressor P21^(WAF1/CIP1) contributed to the synergistic mechanism of the combination *** findings open a novel avenue for the treatment of KRAS-mutant lung cancer.

关键词： synthetic lethality KRAS Polo-like kinase 1 RhoA/Rho kinase Combination therapy

Epigenetic silencing schlafen-11 sensitizes esophageal cancer to ATM inhibitor

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World Journal of Gastrointestinal Oncology 2024年第5期16卷 2060-2073页

作者： Jing Zhou Mei-Ying Zhang Ai-Ai Gao Cheng Zhu Tao He James G Herman Ming-Zhou Guo School of Medicine NanKai UniversityTianjin 300071China Department of Gastroenterology and Hepatology The First Medical CenterChinese PLA General HospitalBeijing 100853China Departments of Pathology Characteristic Medical Center of The Chinese People’s Armed Police ForceTianjin 300162China The Hillman Cancer Center University of Pittsburgh Cancer InstitutePittsburghPA 15213United States National Key Laboratory of Kidney Diseases Chinese PLA General HospitalBeijing 100853China

BACKGROUND Targeting DNA damage response(DDR)pathway is a cutting-edge *** has been reported that Schlafen-11(SLFN11)contributes to increase chemosensitivity by participating in ***,the detailed mechanism is *** To investigate the role of SLFN11 in DDR and the application of synthetic lethal in esophageal cancer with SLFN11 *** To reach the purpose,eight esophageal squamous carcinoma cell lines,142 esophageal dysplasia(ED)and 1007 primary esophageal squamous cell carcinoma(ESCC)samples and various techniques were utilized,including methylationspecific polymerase chain reaction,CRISPR/Cas9 technique,Western blot,colony formation assay,and xenograft mouse *** Methylation of SLFN11 was exhibited in 9.15%of(13/142)ED and 25.62%of primary(258/1007)ESCC cases,and its expression was regulated by promoter region ***11 methylation was significantly associated with tumor differentiation and tumor size(both P<0.05).However,no significant associations were observed between promoter region methylation and age,gender,smoking,alcohol consumption,TNM stage,or lymph node *** DNA damaged model induced by low dose cisplatin,SLFN11 was found to activate non-homologous end-joining and ATR/CHK1 signaling pathways,while inhibiting the ATM/CHK2 signaling *** silencing of SLFN11 was found to sensitize the ESCC cells to ATM inhibitor(AZD0156),both in vitro and in *** SLFN11 is frequently methylated in human *** of SLFN11 is sensitive marker of ATM inhibitor in ESCC.

关键词： Schlafen-11 Esophageal squamous cell carcinoma DNA methylation synthetic lethality AZD0156

Targeting DNA repair for cancer treatment: Lessons from PARP inhibitor trials

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Oncology Research 2023年第4期31卷 405-421页

作者： DHANYA K.NAMBIAR DEEPALI MISHRA RANA P.SINGH Department of Radiation Oncology Stanford University School of MedicineStanfordCA94305USA Cancer Biology Laboratory School of Life SciencesJawaharlal Nehru UniversityNew Delhi110067India Special Centre for Systems Medicine Jawaharlal Nehru UniversityNew Delhi10067India

Ionizing radiation is frequently used to treat solid tumors,as it causes DNA damage and kill cancer ***,damaged DNA is repaired involving poly-(ADP-ribose)polymerase-1(PARP-1)causing resistance to radiation ***,PARP-1 represents an important target in multiple cancer types,including prostate *** is a nuclear enzyme essential for single-strand DNA breaks *** PARP-1 is lethal in a wide range of cancer cells that lack the homologous recombination repair(HR)*** article provides a concise and simplified overview of the development of PARP inhibitors in the laboratory and their clinical *** focused on the use of PARP inhibitors in various cancers,including prostate *** also discussed some of the underlying principles and challenges that may affect the clinical efficacy of PARP inhibitors.

关键词： PARP inhibitors synthetic lethality DNA repair BRCA mutations

The role of PARP1 in the DNA damage response and its application in tumor therapy

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Frontiers of Medicine 2012年第2期6卷 156-164页

作者： Zhifeng Wang Fengli Wang Tieshan Tang Caixia Guo Laboratory of Disease Genomics and Individual Medicine Beijing Institute of GenomicsChinese Academy of SciencesBeijing 100029China State Key Laboratory of Biomembrane and Membrane Biotechnology Institute of ZoologyChinese Academy of SciencesBeijing 100101China

Single-strand break repair protein poly(ADP-ribose)polymerase 1(PARP1)catalyzes the poly(ADPribosyl)ation of many key proteins in vivo and thus plays important roles in multiple DNA damage response pathways,rendering it a promising target in cancer *** tumor-suppressor effects of PARP inhibitors have attracted significant interest for development of novel cancer ***,recent evidence indicated that the underlying mechanism of PARP inhibitors in tumor therapy is more complex than previously *** present review will focus on recent progress on the role of PARP1 in the DNA damage response and PARP inhibitors in cancer *** emerging resistance of BRCA-deficient tumors to PARP inhibitors is also briefly discussed from the perspective of DNA damage and *** recent research advances will inform the selection of patient populations who can benefit from the PARP inhibitor treatment and development of effective drug combination strategies.

关键词： PARP1 synthetic lethality PARP inhibitor DNA repair cancer NHEJ

Mutant KRAS as a critical determinant of the therapeutic response of colorectal cancer

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Genes & Diseases 2015年第1期2卷 4-12页

作者： Kyle Knickelbein Lin Zhang University of Pittsburgh Cancer Institute Departments of Pharmacology&Chemical BiologyUniversity of Pittsburgh School of MedicinePittsburghPA 15213USA

Mutations in the KRAS oncogene represent one of the most prevalent genetic alterations in colorectal cancer(CRC),the third leading cause of cancer-related death in the *** addition to their well-characterized function in driving tumor progression,KRAS mutations have been recognized as a critical determinant of the therapeutic response of *** studies demonstrate that KRAS-mutant tumors are intrinsically insensitive to clinically-used epidermal growth factor receptor(EGFR)targeting antibodies,including cetuximab and *** resistance to the anti-EGFR therapy was found to be associated with enrichment of KRAS-mutant tumor ***,the underlying molecular mechanism of mutant-KRAS-mediated therapeutic resistance has remained *** intensive efforts,directly targeting mutant KRAS has been largely *** review summarizes the recent advances in understanding the biological function of KRAS mutations in determining the therapeutic response of CRC,highlighting several recently developed agents and strategies for targeting mutant KRAS,such as synthetic lethal interactions.

关键词： Colorectal cancer EGFR KRAS synthetic lethality Targeted therapy

Recent advancements in PARP inhibitors-based targeted cancer therapy

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Precision Clinical Medicine 2020年第3期3卷 187-201页

作者： Ping Zhou Justin Wang Daniel Mishail Cun-Yu Wang Laboratory of Molecular Signaling Division of Oral Biology and MedicineSchool of DentistryUCLALos AngelesCA 90095USA Jonsson Comprehensive Cancer Center UCLALos AngelesCA 90095USA Department of Bioengineering Henry Samueli School of Engineering and Applied ScienceUCLALos AngelesCA 90095USA

Poly(ADP-ribose)polymerase inhibitors(PARPi)are a new class of agents with unparalleled clinical achievement for driving synthetic lethality in BRCA-deficient *** FDA approval of PARPi has motivated clinical trials centered around the optimization of PARPi-associated therapies in a variety of BRCA-deficient *** review highlights recent advancements in understanding the molecular mechanisms of PARP‘trapping’and synthetic *** attention is placed on the potential extension of PARPi therapies from BRCA-deficient patients to populations with other homologous recombination-deficient backgrounds,and common characteristics of PARPi and non-homologous end-joining have been *** synergistic antitumor effect of combining PARPi with various immune checkpoint blockades has been explored to evaluate the potential of combination therapy in attaining greater therapeutic *** has shed light onto the differing classifications of PARPi as well as the factors that result in altered PARPi ***,acquired chemoresistance is a crucial issue for clinical application of *** molecularmechanisms underlying PARPi resistance and potential overcoming strategies are discussed.

关键词： PARP1 classifications of PARP inhibitors BRCA1/2 synthetic lethality acquired chemoresistance to PARP inhibitors immunotherapy

BET inhibition induces GDH1-dependent glutamine metabolic remodeling and vulnerability in liver cancer

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Life Metabolism 2024年第4期3卷 28-41页

作者： Wen Mi Jianwei You Liucheng Li Lingzhi Zhu Xinyi Xia Li Yang Fei Li Yi Xu Junfeng Bi Pingyu Liu Li Chen Fuming Li Shanghai Key Laboratory of Metabolic Remodeling and Health Institute of Metabolism and Integrative BiologyFudan UniversityShanghai 200438China Human Phenome Institute Zhangjiang Fudan International Innovation CenterFudan UniversityShanghai 201203China Department of Pathology School of Basic Medical SciencesFudan UniversityShanghai 200032China Frontier Innovation Center School of Basic Medical SciencesFudan UniversityShanghai 200032China

Bromodomain and extra-terminal domain(BET)proteins,which function partly through MYC proto-oncogene(MYC),are critical epigenetic readers and emerging therapeutic targets in *** and how BET inhibition simultaneously induces metabolic remodeling in cancer cells remains *** we find that even transient BET inhibition by JQ-1 and other pan-BET inhibitors(pan-BETis)blunts liver cancer cell proliferation and tumor *** inhibition decreases glycolytic gene expression but enhances mitochondrial glucose and glutamine oxidative metabolism revealed by metabolomics and isotope labeling ***,BET inhibition downregulates miR-30a to upregulate glutamate dehydrogenase 1(GDH1)independent of MYC,which producesα-ketoglutarate for mitochondrial oxidative phosphorylation(OXPHOS).Targeting GDH1 or OXPHOS is synthetic lethal to BET inhibi-tion,and combined BET and OXPHOS inhibition therapeutically prevents liver tumor growth in vitro and in ***,we uncover an important epigenetic-metabolic crosstalk whereby BET inhibition induces MYC-independent and GDH1-dependent glutamine metabolic remodeling that can be exploited for innovative combination therapy of liver cancer.

关键词： BET glutamate dehydrogenase 1 oxidative phosphorylation glutamine metabolism synthetic lethality

Mechanism of RBBP8-mediated homologous recombination repair in gastric cancer synthetic lethal

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Chronic Diseases and Translational Medicine 2023年第3期9卷 250-257页

作者： Yang Yu Shuxia Wang Yanhua Yin Guangsheng Wang Department of Gastroenterology Beijing Friendship HospitalBeijingChina Department of Oncology Beijing Aviation General HospitalBeijingChina Department of Pathology Liaocheng People's HospitalLiaochengShandongChina

Background:It is of great clinical significance to further explore new strategies and potential combined therapeutic targets for gastric *** study aimed to investigate the synthetic lethal effect of RBBP8 molecular intervention combined with a poly ADP ribose polymerase(PARP)inhibitor in non-BRCA mutant gastric cancer and clarify the mechanism by which RBBP8 regulates homologous recombination ***:The role of RBBP8 in DNA damage repair was observed using bioinformatic analysis,western blot analysis,and *** synthetic lethal effect was verified using 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium,inner salt(MTS)and flow cytometry apoptosis ***:Among the patients with gastric cancer treated with chemotherapy,the prognosis of patients with high RBBP8 expression levels was worse(homologous recombination[HR]=1.54,p=0.028).RBBP8 knockdown induced DNA damage and had a synergistic effect with PARP inhibitor treatment on cell viability inhibition and cell apoptosis in AGS(generic code for human gastric adenocarcinoma cells)(t=11.154,psynthetic lethal effect with PARP inhibitor treatment in gastric cancer cells.

关键词： gastric cancer homologous recombination repair molecular mechanism RBBP8 synthetic lethality