Synthetic lethality is becoming more and more important in the precise treatment of oncology.Malignant tumors caused by gene mutations involve a complex DNA signaling process,and inhibition of DNA signaling in differe...Synthetic lethality is becoming more and more important in the precise treatment of oncology.Malignant tumors caused by gene mutations involve a complex DNA signaling process,and inhibition of DNA signaling in different ways may more effectively control the occurrence and development of tumors.Inhibition of tumor paired lethal genes effectively kills tumor cells,and more and more novel drugs that inhibit tumors are developing in this direction.This article reviews the synthetic lethal theory and discusses selection of drugs to target mutated genes in common solid tumors.The synthetic lethal gene pairs,representative targeted drugs,and related characteristics of four tumor types:lung cancer,breast cancer,colon cancer and prostate cancer,are systematically reviewed.展开更多
Among the numerous oncogenes involved in human cancers, KRAS represents the most studied and best characterized cancerrelated genes.Several therapeutic strategies targeting oncogenic KRAS(KRASonc) signaling pathways h...Among the numerous oncogenes involved in human cancers, KRAS represents the most studied and best characterized cancerrelated genes.Several therapeutic strategies targeting oncogenic KRAS(KRASonc) signaling pathways have been suggested,including the inhibition of synthetic lethal interactions, direct inhibition of KRASonc itself, blockade of downstream KRASonc effectors, prevention of post-translational KRASonc modifications, inhibition of the induced stem cell-like program, targeting of metabolic peculiarities, stimulation of the immune system, inhibition of inflammation, blockade of upstream signaling pathways,targeted RNA replacement, and oncogene-induced senescence.Despite intensive and continuous efforts, KRASonc remains an elusive target for cancer therapy.To highlight the progress to date, this review covers a collection of studies on therapeutic strategies for KRAS published from 1995 to date.An overview of the path of progress from earlier to more recent insights highlight novel opportunities for clinical development towards KRASonc-signaling targeted therapeutics.展开更多
Androgen deprivation therapy(ADT)has been the standard of care for the last 75 years in metastatic hormone sensitive prostate cancer(PCa).However,this approach is rarely curative.Recent clinical trials have demonstrat...Androgen deprivation therapy(ADT)has been the standard of care for the last 75 years in metastatic hormone sensitive prostate cancer(PCa).However,this approach is rarely curative.Recent clinical trials have demonstrated that ADT combined with other agents,notably docetaxel and abiraterone,lead to improved survival.The mechanisms surrounding this improved cancer outcomes are incompletely defined.The response of cancer cells to ADT includes apoptosis and cell death,but a significant fraction remains viable.Our laboratory has demonstrated both in vitro and in vivo that cellular senescence occurs in a subset of these cells.Cellular senescence is a phenotype characterized by cell cycle arrest,senescenceassociated b-galactosidase(SA-b-gal),and a hypermetabolic state.Positive features of cellular senescence include growth arrest and immune stimulation,although persistence may release cytokines and growth factors that are detrimental.Senescent tumor cells generate a catabolic state with increased glycolysis,protein turnover and other metabolic changes that represent targets for drugs,like metformin,to be applied in a synthetic lethal approach.This review examines the response to ADT and the putative role of cellular senescence as a biomarker and therapeutic target in this context.展开更多
Aurora kinase A(Aurora-A),a serine/threonine kinase,plays a pivotal role in various cellular processes,including mitotic entry,centrosome maturation and spindle formation.Overexpression or gene-amplification/mutation ...Aurora kinase A(Aurora-A),a serine/threonine kinase,plays a pivotal role in various cellular processes,including mitotic entry,centrosome maturation and spindle formation.Overexpression or gene-amplification/mutation of Aurora-A kinase occurs in different types of cancer,including lung cancer,colorectal cancer,and breast cancer.Alteration of Aurora-A impacts multiple cancer hallmarks,especially,immortalization,energy metabolism,immune escape and cell death resistance which are involved in cancer progression and resistance.This review highlights the most recent advances in the oncogenic roles and related multiple cancer hallmarks of Aurora-A kinase-driving cancer therapy resistance,including chemoresistance(taxanes,cisplatin,cyclophosphamide),targeted therapy resistance(osimertinib,imatinib,sorafenib,etc.),endocrine therapy resistance(tamoxifen,fulvestrant) and radioresistance.Specifically,the mechanisms of Aurora-A kinase promote acquired resistance through modulating DNA damage repair,feedback activation bypass pathways,resistance to apoptosis,necroptosis and autophagy,metastasis,and stemness.Noticeably,our review also summarizes the promising synthetic lethality strategy for Aurora-A inhibitors in RB1,ARID1A and MYC gene mutation tumors,and potential synergistic strategy for m TOR,PAK1,MDM2,MEK inhibitors or PD-L1 antibodies combined with targeting Aurora-A kinase.In addition,we discuss the design and development of the novel class of Aurora-A inhibitors in precision medicine for cancer treatment.展开更多
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 US.In addition to their well-characterized functi...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 US.In addition to their well-characterized function in driving tumor progression,KRAS mutations have been recognized as a critical determinant of the therapeutic response of CRC.Recent studies demonstrate that KRAS-mutant tumors are intrinsically insensitive to clinically-used epidermal growth factor receptor(EGFR)targeting antibodies,including cetuximab and panitumumab.Acquired resistance to the anti-EGFR therapy was found to be associated with enrichment of KRAS-mutant tumor cells.However,the underlying molecular mechanism of mutant-KRAS-mediated therapeutic resistance has remained unclear.Despite intensive efforts,directly targeting mutant KRAS has been largely unsuccessful.This 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.展开更多
文摘Synthetic lethality is becoming more and more important in the precise treatment of oncology.Malignant tumors caused by gene mutations involve a complex DNA signaling process,and inhibition of DNA signaling in different ways may more effectively control the occurrence and development of tumors.Inhibition of tumor paired lethal genes effectively kills tumor cells,and more and more novel drugs that inhibit tumors are developing in this direction.This article reviews the synthetic lethal theory and discusses selection of drugs to target mutated genes in common solid tumors.The synthetic lethal gene pairs,representative targeted drugs,and related characteristics of four tumor types:lung cancer,breast cancer,colon cancer and prostate cancer,are systematically reviewed.
基金supported by the European Network on Noonan Syndrome and Related Disorders (NSEuroNet, Grant No.01GM1602B)the German Federal Ministry of Education and Research(BMBF): German Network of RASopathy Research (GeNeRARe, Grant No.01GM1519D & 01GM1902C)
文摘Among the numerous oncogenes involved in human cancers, KRAS represents the most studied and best characterized cancerrelated genes.Several therapeutic strategies targeting oncogenic KRAS(KRASonc) signaling pathways have been suggested,including the inhibition of synthetic lethal interactions, direct inhibition of KRASonc itself, blockade of downstream KRASonc effectors, prevention of post-translational KRASonc modifications, inhibition of the induced stem cell-like program, targeting of metabolic peculiarities, stimulation of the immune system, inhibition of inflammation, blockade of upstream signaling pathways,targeted RNA replacement, and oncogene-induced senescence.Despite intensive and continuous efforts, KRASonc remains an elusive target for cancer therapy.To highlight the progress to date, this review covers a collection of studies on therapeutic strategies for KRAS published from 1995 to date.An overview of the path of progress from earlier to more recent insights highlight novel opportunities for clinical development towards KRASonc-signaling targeted therapeutics.
基金The study was supported by DOD Prostate Cancer Research Program PC150221,R.Stephenson Family Fund.
文摘Androgen deprivation therapy(ADT)has been the standard of care for the last 75 years in metastatic hormone sensitive prostate cancer(PCa).However,this approach is rarely curative.Recent clinical trials have demonstrated that ADT combined with other agents,notably docetaxel and abiraterone,lead to improved survival.The mechanisms surrounding this improved cancer outcomes are incompletely defined.The response of cancer cells to ADT includes apoptosis and cell death,but a significant fraction remains viable.Our laboratory has demonstrated both in vitro and in vivo that cellular senescence occurs in a subset of these cells.Cellular senescence is a phenotype characterized by cell cycle arrest,senescenceassociated b-galactosidase(SA-b-gal),and a hypermetabolic state.Positive features of cellular senescence include growth arrest and immune stimulation,although persistence may release cytokines and growth factors that are detrimental.Senescent tumor cells generate a catabolic state with increased glycolysis,protein turnover and other metabolic changes that represent targets for drugs,like metformin,to be applied in a synthetic lethal approach.This review examines the response to ADT and the putative role of cellular senescence as a biomarker and therapeutic target in this context.
基金supported by the Natural Science Foundation of Hebei Province(No.H2020209284,China,Dayong Zheng)Scientific Research Foundation of Higher Education Institutions of Hebei Province(No.QN2021120,Dayong Zheng)+1 种基金Department of Science and Technology of Liaoning province(No.2020-MS-225,China,Jun Li)the Montefiore Einstein Cancer Center grant(NCI P30CA013330,USA,Edward Chu)。
文摘Aurora kinase A(Aurora-A),a serine/threonine kinase,plays a pivotal role in various cellular processes,including mitotic entry,centrosome maturation and spindle formation.Overexpression or gene-amplification/mutation of Aurora-A kinase occurs in different types of cancer,including lung cancer,colorectal cancer,and breast cancer.Alteration of Aurora-A impacts multiple cancer hallmarks,especially,immortalization,energy metabolism,immune escape and cell death resistance which are involved in cancer progression and resistance.This review highlights the most recent advances in the oncogenic roles and related multiple cancer hallmarks of Aurora-A kinase-driving cancer therapy resistance,including chemoresistance(taxanes,cisplatin,cyclophosphamide),targeted therapy resistance(osimertinib,imatinib,sorafenib,etc.),endocrine therapy resistance(tamoxifen,fulvestrant) and radioresistance.Specifically,the mechanisms of Aurora-A kinase promote acquired resistance through modulating DNA damage repair,feedback activation bypass pathways,resistance to apoptosis,necroptosis and autophagy,metastasis,and stemness.Noticeably,our review also summarizes the promising synthetic lethality strategy for Aurora-A inhibitors in RB1,ARID1A and MYC gene mutation tumors,and potential synergistic strategy for m TOR,PAK1,MDM2,MEK inhibitors or PD-L1 antibodies combined with targeting Aurora-A kinase.In addition,we discuss the design and development of the novel class of Aurora-A inhibitors in precision medicine for cancer treatment.
基金supported in part by the graduate student fellowship from the Department of Pharmacology&Chemical BiologyResearch in L.Z.’s lab is supported by the National Institute of Health grants R01CA106348 and R01CA172136.
文摘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 US.In addition to their well-characterized function in driving tumor progression,KRAS mutations have been recognized as a critical determinant of the therapeutic response of CRC.Recent studies demonstrate that KRAS-mutant tumors are intrinsically insensitive to clinically-used epidermal growth factor receptor(EGFR)targeting antibodies,including cetuximab and panitumumab.Acquired resistance to the anti-EGFR therapy was found to be associated with enrichment of KRAS-mutant tumor cells.However,the underlying molecular mechanism of mutant-KRAS-mediated therapeutic resistance has remained unclear.Despite intensive efforts,directly targeting mutant KRAS has been largely unsuccessful.This 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.
