Emerging roles of Aurora-A kinase in cancer therapy resistance

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 mTOR, 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.

Research progress on genome-guided precision oncology and development ideas of antitumor Chinese medicine / 中国中药杂志

Genome-guided oncology refers to a new treatment concept that transcends histological classification and pathological ty-ping and uses drugs according to the genetic characteristics of tumors. New drug development technology and clinical trial design based on this concept provide new ideas for the clinical application of precision oncology. The multi-component and multi-target characteristics of Chinese medicine provide rich resources for the development of tumor-targeting drugs from natural products, and the design of the master protocol trial aiming at the characteristics of precision oncology supports the rapid clinical screening of effective tumor-targeting drugs. The emergence of the synthetic lethality strategy breaks through the bottleneck that the drug can only target the oncogene but cannot do anything to the tumor suppressor gene with the loss-of-function mutation in the past. With the rapid development of high-throughput sequencing technology, the cost of sequencing is also decreasing. For the development of tumor-targeting drugs, how to keep up with the update speed of target information is a difficult problem of concern. Based on the integration of innovative ideas and me-thods of precision oncology, network pharmacology, and synthetic lethality strategy on synthetic lethal interaction network of antitumor Chinese medicine compatibility formula design, and the combination of improvement of innovative clinical trial methods, such as master protocol trial, basket trial, and umbrella trial, unique advantages of Chinese medicine are expected to be exerted beyond the antibody-based drugs and small molecule-based drugs and corresponding targeted drugs are potentially developed for clinical application.

Evidence of a synthetic lethality interaction between SETDB1 histone methyltransferase and CHD4 chromatin remodeling protein in a triple negative breast cancer cell line

During the tumorigenic process, cancer cells may become overly dependent on the activity of backup cellular pathways for their survival, representing vulnerabilities that could be exploited as therapeutic targets. Certain molecular vulnerabilities manifest as a synthetic lethality relationship, and the identification and characterization of new synthetic lethal interactions may pave the way for the development of new therapeutic approaches for human cancer. Our goal was to investigate a possible synthetic lethal interaction between a member of the Chromodomain Helicase DNA binding proteins family (CHD4) and a member of the histone methyltransferases family (SETDB1) in the molecular context of a cell line (Hs578T) representing the triple negative breast cancer (TNBC), a subtype of breast cancer lacking validated molecular targets for treatment. Therefore, we employed the CRISPR-Cas9 gene editing tool to individually or simultaneously introduce indels in the genomic loci corresponding to the catalytic domains of SETDB1 and CHD4 in the Hs578T cell line. Our main findings included: a) introduction of indels in exon 22 of SETDB1 sensitized Hs578T to the action of the genotoxic chemotherapy doxorubicin; b) by sequentially introducing indels in exon 22 of SETDB1 and exon 23 of CHD4 and tracking the percentage of the remaining wild-type sequences in the mixed cell populations generated, we obtained evidence of the existence of a synthetic lethality interaction between these genes. Considering the lack of molecular targets in TNBC, our findings provided valuable insights for development of new therapeutic approaches not only for TNBC but also for other cancer types.

Cyclin-dependent kinases-based synthetic lethality: Evidence, concept, and strategy

Synthetic lethality is a proven effective antitumor strategy that has attracted great attention. Large-scale screening has revealed many synthetic lethal genetic phenotypes, and relevant small-molecule drugs have also been implemented in clinical practice. Increasing evidence suggests that CDKs, constituting a kinase family predominantly involved in cell cycle control, are synthetic lethal factors when combined with certain oncogenes, such as

Targeting "undruggable" c-Myc protein by synthetic lethality / 医学前沿

Synthetic lethal screening, which exploits the combination of mutations that result in cell death, is a promising method for identifying novel drug targets. This method provides a new avenue for targeting "undruggable" proteins, such as c-Myc. Here, we revisit current methods used to target c-Myc and discuss the important functional nodes related to c-Myc in non-oncogene addicted network, whose inhibition may cause a catastrophe for tumor cell destiny but not for normal cells. We further discuss strategies to identify these functional nodes in the context of synthetic lethality. We review the progress and shortcomings of this research field and look forward to opportunities offered by synthetic lethal screening to treat tumors potently.

Research progress in targeting homologous recombination repair for tumor therapy / 药学学报

Applying poly(ADP-ribose) polymerase inhibitors (PARPi) to the treatment of cancers with homologous recombination deficiency (HRDness) has been a great advance in the field of molecular therapeutics. However, in the clinic patients lacking the specific mutations or developing reverse mutations in the process of PARPi treatment may not benefit from PARPi monotherapy. Therefore, targeting homologous recombination (HR) repair with molecularly targeted agents is becoming an attractive research focus and is raising the concept of "chemical HRDness". HR repair is an evolutionarily conserved and extensively regulated process that employs sister chromatids as the template to repair DNA double-strand breaks with high fidelity. In addition to directly targeting HR components, modulation of regulatory pathways controlling HR repair is effective in achieving the "HRDness" phenotype; this includes modulation of the cell cycle checkpoint regulatory pathway, the phosphatidylinositol 3-kinase (PI3K) signaling pathway, the chromatin remodeling pathway, etc. Targeting HR repair can not only result in "synthetic lethality" when combined with PARPi, but also sensitizes cancers to traditional radio/chemotherapy and novel immunotherapy. In this review we describe the HR repair pathway and its regulatory pathways, summarize the preclinical and clinical outcomes of targeting HR repair, discuss the remaining problems in this field and provide a prospective on its application in tumor therapy.

Current status of synthetic lethality effects in cancer research / 中国肿瘤临床

Most carcinogenic mutations, including those causing a loss of function, are not directly "druggable" with traditional small-molecule inhibitors, such as targeted drugs. Thus, despite our growing cognition of carcinogenic mutations that drive tumor progres-sion, there are still problems regarding targeted therapy for tumors. The application of synthetic lethality effects is expected to be-come a new breakthrough in tumor-targeted therapy. Therefore, identifying a combination of genetic mutations that generate synthet-ic lethality effects plays important roles in targeted therapy for tumors. This article reviews the origin and development of synthetic le-thality effects, the forms of interaction, related screening techniques, clinical treatment strategies, and significance and challenges.

Human papillomavirus and genome instability: from productive infection to cancer

Infection with high oncogenic risk human papillomavirus types is the etiological factor of cervical cancer and a major cause of other epithelial malignancies, including vulvar, vaginal, anal, penile and head and neck carcinomas. These agents affect epithelial homeostasis through the expression of specific proteins that deregulate important cellular signaling pathways to achieve efficient viral replication. Among the major targets of viral proteins are components of the DNA damage detection and repair machinery. The activation of many of these cellular factors is critical to process viral genome replication intermediates and, consequently, to sustain faithful viral progeny production. In addition to the important role of cellular DNA repair machinery in the infective human papillomavirus cycle, alterations in the expression and activity of many of its components are observed in human papillomavirus-related tumors. Several studies from different laboratories have reported the impact of the expression of human papillomavirus oncogenes, mainly E6 and E7, on proteins in almost all the main cellular DNA repair mechanisms. This has direct consequences on cellular transformation since it causes the accumulation of point mutations, insertions and deletions of short nucleotide stretches, as well as numerical and structural chromosomal alterations characteristic of tumor cells. On the other hand, it is clear that human papillomavirus-transformed cells depend on the preservation of a basal cellular DNA repair activity level to maintain tumor cell viability. In this review, we summarize the data concerning the effect of human papillomavirus infection on DNA repair mechanisms. In addition, we discuss the potential of exploiting human papillomavirus-transformed cell dependency on DNA repair pathways as effective antitumoral therapies.

Targeting DNA damage response pathway: recent progress of PARP inhibitors in cancer therapy / 中国药理学通报

Genomic instability is one of the most pervasive characteristics of cancer cells,and DNA damage response (DDR) pathway plays a crucial role in genomic stability.The DDR pathway is a complex signaling network,which involves cell DNA repair,apoptosis and cell cycle regulation.Deficiencies in these repair pathways can result in several different genetic disorders,including cancer.Targeted therapy based on inhibiting the DDR pathway in cancers offers a novel therapy strategy for patients with tumors lacking specific DDR functions.Many small-mole-cule compounds targeting DDR pathway are typically developed for solid cancer therapy.The poly (ADP-ribose) polymerase (PARP) inhibitor is a kind of DDR inhibitors which exploits the principle of synthetic lethality to selectively kill cancer cells.This review highlights the molecular mechanisms of PARP inhibitor action,the progress of PARP inhibitors in cancer therapy,drug resistance and the challenge of PARP inhibitor in the future.

Poly(ADP-ribose)polymerase inhibitors for ovarian cancer treatment: Research advances / 国际药学研究杂志

Ovarian cancer is the leading cause of death in women suffering from cancer, with a high mortality rate in gynecological cancer. Poly(ADP-ribose)polymerase(PARP)inhibitors cause targeted tumor cell death in homologous recombination(HR)-deficient cancers, including breast cancer susceptibility gene(BRCA)tumors, and the mechanism is called “synthetic lethality”. At present, there are three PARP inhibitors approved by FDA for the treatment of advanced ovarian cancer with BRCA-mutation. This paper reviews the role of PARP inhibitors in the treatment of ovarian cancer in clinical trial, elaborates the therapeutic mechanism of PARP inhibitors, and lights the way for the development of anti-ovarian cancer drugs.

The Mechanism Study of Micro-substance of Chinese Medicine——The Discovery and Elucidation of Effective Substance and Mechanism of Chinese Medicine via the Theory of Synthetic Lethality / 世界科学技术-中医药现代化

The elaboration of the mechanism and pharmacodynamic substance are the main obstacles to the modernization of Chinese medicine.The rich ingredient of Chinese medicine is almost attention,with a research strategy of forward pharmacology.This strategy often neglects the study of trace components of Chinese medicine.Synthetic lethality,a extremely complex gene interactions,is to magnify the effects of the co-regulation of biological effects (＞ 1 000 times).The theory of synthetic lethality has achieved good results in the development of anti-tumor drugs,including the discovery of PARP inhibitors,the clinical use of chemotherapy drug addition and attenuation combination.In view of this,this research model may be used to elucidate trace effective substance.Based on the reverse thinking of "targetcomponent-effect"and clear synergistic targets,the mechanism of traces and weak-potency substance of traditional Chinese medicine was studied,and the synergistic combination of potential was found.

Poly(ADP-ribose)polymerase inhibitors for ovarian cancer treatment:research advances / 国际药学研究杂志

Ovarian cancer is the leading cause of death in women suffering from cancer,with a high mortality rate in gyneco?logical cancer. Poly(ADP-ribose)polymerase(PARP)inhibitors cause targeted tumor cell death in homologous recombination(HR)-deficient cancers,including breast cancer susceptibility gene(BRCA)tumors,and the mechanism is calledsynthetic lethality. At present,there are three PARP inhibitors approved by FDA for the treatment of advanced ovarian cancer with BRCA-mutation. This pa?per reviews the role of PARP inhibitors in the treatment of ovarian cancer in clinical trial,elaborates the therapeutic mechanism of PARP inhibitors,and lights the way for the development of anti-ovarian cancer drugs.

Research progress in synthetic lethality targeting DNA repair defects / 肿瘤

The concept of synthetic lethality is defined as a genetic interaction of two non-allelic and non-lethal genes that when mutated simultaneously results in cell death, which has been proposed as a potential way to develop novel antitumor approaches. A new therapeutic approach targeting DNA repair defective genes may remarkably promote the antitumor efficacy based on the mechanism of tumorigenesis induced by DNA repair defects. Previous studies have demontrated that BRCA1 (breast cancer susceptibility gene 1)/BRCA2 or PTEN (phosphatase and tensin homolog deleted on chromosome 10) gene mutation with PARP [poly(ADP-ribose) polymerase] inhibitors could lead to killing effect in cancer cells; deletion of MSH2 (mutS homolog 2) gene with inhibiton of proofreading activity of DNA polβ (polymerase β) and the deletion of MLH1 (mutL homolog 1) gene with inhibiton of proofreading activity of DNA polγ could both lead to killing effect in cancer cells with MMR (mismatch repair) deficiency. PINK1 (PTEN-induced putative kinase 1) may be a potential therapeutic target for the treatment of MMR-deficient cancers with deletion of MSH2, MLH1 or MSH6 gene based on the theory of synthetic lethality. This review descibes the synthetic lethality associated with DNA repair defects. Copyright © 2013 by TUMOR.

Advances in research of PARP inhibitors in combination with chemotherapeutic agents in the treatment of malignant tumors / 肿瘤

In recent years, synthetic lethality of PARP [poly (ADP-ribose) polymerase] inhibition in cancers with BRCA1 (breast cancer susceptibility gene 1) and BRCA2 mutations appears to provide a novel, efficient and safe antitumor strategy. It was hypothesized that the mechanism underlying this new antitumor strategy was the inhibition of DNA damage repair leading to cell death. Since the synthetic lethality was confirmed in breast cancer cells by PARP inhibitor intervention, many highly selective and sensitive PARP inhibitors have been developed and applied in clinical trials. Although the effectiveness of PARP inhibitor used as a single agent can be reached in breast cancer and ovarian cancer with BRCA1 / BRCA2 mutation, it is generally advised to use PARP inhibitors in combination with chemotherapeutic agents or radiation therapy. This review is focused on the recent progress in clinical antitumor therapy with PARP inhibitors in combination with common chemotherapeutic agents. Copyright © 2013 by TUMOR.

Advances in the antitumor research of PARP inhibitor / 国际肿瘤学杂志

Poly ADP-Ribose Polymerase(PARP)plays an important role in the detection and repair of DNA damage.Inhibition of the PARP activity in the homologous-recombination defective cancer cell could lead to genomic instability and ultimately cause cell death.In preclinical study PARP inhibitors have demonstrated the capacity of enhancing sensitivity of cancel cells to chemotherapy agents and radiation.PARP inhibitors also showed antitumour potential in early clinical trials as monotherapy or combined with chemotherapy.

Use of a synthetic lethal screen to identify genes related to TIF51A in Saccharomyces cerevisiae

The putative eukaryotic translation initiation factor 5A (eIF5A) is an essential protein for cell viability and the only cellular protein known to contain the unusual amino acid residue hypusine. eIF5A has been implicated in translation initiation, cell proliferation, nucleocytoplasmic transport, mRNA decay, and actin polarization, but the precise biological function of this protein is not clear. However, eIF5A was recently shown to be directly involved with the translational machinery. A screen for synthetic lethal mutations was carried out with one of the temperature-sensitive alleles of TIF51A (tif51A-3) to identify factors that functionally interact with eIF5A and revealed the essential gene YPT1. This gene encodes a small GTPase, a member of the rab family involved with secretion, acting in the vesicular trafficking between endoplasmatic reticulum and the Golgi. Thus, the synthetic lethality between TIF51A and YPT1 may reveal the connection between translation and the polarized distribution of membrane components, suggesting that these proteins work together in the cell to guarantee proper protein synthesis and secretion necessary for correct bud formation during G1/S transition. Future studies will investigate the functional interaction between eIF5A and Ypt1 in order to clarify this involvement of eIF5A with vesicular trafficking.