Role of apurinic/apyrimidinic nucleases in the regulation of homologous recombination in myeloma: mechanisms and translational significance

Kumar, Subodh; Talluri, Srikanth; Pal, Jagannath; Yuan, Xiaoli; Lu, Renquan; Nanjappa, Puru; Samur, Mehmet K.; Munshi, Nikhil C.; Shammas, Masood A.

doi:10.1038/s41408-018-0129-9

Cited by 45 publications

(63 citation statements)

References 52 publications

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“…Consistently, we have demonstrated that inhibition of HR in EAC cells, inhibits genomic instability 14 and tumor growth 17 . Our recent data in multiple myeloma has also demonstrated that inhibition of APEX1 nuclease, a gene which drives genomic evolution in myeloma, increases cytotoxicity while inhibiting genomic instability caused by a chemotherapeutic agent 41 . We have made similar observations when HR inhibitors are used in combination with other chemotherapeutic agents (unpublished data).…”

Section: Discussionmentioning

confidence: 89%

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Integrated genomics and comprehensive validation reveal novel drivers of genomic evolution in esophageal adenocarcinoma

Kumar

Buon

Talluri

et al. 2020

Preprint

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Identification of genes driving genomic evolution can provide novel targets for cancer treatment and prevention. Here we show identification of a genomic instability gene signature, using an integrated genomics approach. Elevated expression of this signature correlated with poor survival in esophageal adenocarcinoma (EAC) as well as three other human cancers. Knockout and overexpression screens confirmed the relevance of this signature to genomic instability. Indepth evaluation of TTK (a kinase), TPX2 (spindle assembly factor) and RAD54B (recombination protein) further confirmed their role in genomic instability and tumor growth. Mutational signatures identified by whole genome sequencing and functional studies demonstrated that DNA damage and homologous recombination were common mechanisms of genomic instability induced by these genes. Consistently, a TTK inhibitor impaired EAC cell growth in vivo, and increased chemotherapy-induced cytotoxicity while inhibiting genomic instability in surviving cells. Thus inhibitors of TTK and other genes identified in this study have potential to inhibit/delay genomic evolution and tumor growth. Such inhibitors also have potential to increase chemotherapy-induced cytotoxicity while reducing its harmful genomic impact in EAC and possibly other cancers.

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Section: Discussionmentioning

confidence: 89%

“…HR activity was measured in a plasmid substrate, using a luminescence-based assay reported by us previously 14,17,41 .…”

Section: Methodsmentioning

confidence: 99%

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Integrated genomics and comprehensive validation reveal novel drivers of genomic evolution in esophageal adenocarcinoma

Kumar

Buon

Talluri

et al. 2020

Preprint

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“…Consistent with this, our series of studies using Xenopus egg extract system suggest that APE2 plays a direct role in SSB repair via the 3′-5′ SSB end resection 11,26,43 . Of note, gene expression of APE2 and APE1 has been found up-regulated in multiple myeloma (MM) patients and MM cells, which may lead to dysregulation of HR via regulating Rad51 expression 32 . These new evidences suggest that APE2 contributes to genome integrity via different mechanisms.…”

Section: Discussionmentioning

confidence: 99%

“…Accumulating evidence has suggested that abnormal expression of APE1 is implicated in cancer such as gastric cancer and ovarian cancer [29][30][31] . Both APE1 and APE2 have previously been found to be upregulated in multiple myeloma cell lines 32 . However, it remains unknown whether the expression of APE2 in patient-derived tumor tissues is altered when compared with non-malignant tissues across multiple cancer types.…”

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confidence: 97%

Genomic alterations and abnormal expression of APE2 in multiple cancers

Jensen

Shi

Shan

2020

Sci Rep

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Although APE2 plays essential roles in base excision repair and ATR-Chk1 DNA damage response (DDR) pathways, it remains unknown how the APE2 gene is altered in the human genome and whether APE2 is differentially expressed in cancer patients. Here, we report multiple-cancer analyses of APE2 genomic alterations and mRNA expression from cancer patients using available data from The Cancer Genome Atlas (TCGA). We observe that APE2 genomic alterations occur at ~17% frequency in 14 cancer types (n = 21,769). Most frequent somatic mutations of APE2 appear in uterus (2.89%) and skin (2.47%) tumor samples. Furthermore, APE2 expression is upregulated in tumor tissue compared with matched nonmalignant tissue across 5 cancer types including kidney, breast, lung, liver, and uterine cancers, but not in prostate cancer. We also examine the mRNA expression of 13 other DNA repair and DDR genes from matched samples for 6 cancer types. We show that APE2 mRNA expression is positively correlated with PCNA, APE1, XRCC1, PARP1, Chk1, and Chk2 across these 6 tumor tissue types; however, groupings of other DNA repair and DDR genes are correlated with APE2 with different patterns in different cancer types. Taken together, this study demonstrates alterations and abnormal expression of APE2 from multiple cancers.

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Advanced technological tools to study multidrug resistance in cancer

Luca

Kasas

Garrido

et al. 2020

Drug Resistance Updates

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The complexity of cancer biology and its clinical manifestation are driven by genetic, epigenetic, transcriptomic, proteomic and metabolomic alterations, supported by genomic instability as well as by environmental conditions and lifestyle factors. Although novel therapeutic modalities are being introduced, efficacious cancer therapy is not achieved due to the frequent emergence of distinct mechanisms of multidrug resistance (MDR). Advanced technologies with the potential to identify and characterize cancer MDR could aid in selecting the most efficacious therapeutic regimens and prevent inappropriate treatments of cancer patients. Herein, we aim to present technological tools that will enhance our ability to surmount drug resistance in cancer in the upcoming decade. Some of these tools are already in practice such as next-generation sequencing. Identification of genes and different types of RNAs contributing to the MDR phenotype, as well as their molecular targets, are of paramount importance for the development of new therapeutic strategies aimed to enhance drug response in resistant tumors. Other techniques known for many decades are in the process of adaptation and improvement to study cancer cells' characteristics and biological behavior including atomic force microscopy (AFM) and live-cell imaging. AFM can monitor in real-time single molecules or molecular complexes as well as structural alterations occurring in cancer cells induced upon treatment with various antitumor agents. Cell tracking methodologies and software tools recently progressed towards quantitative analysis of the spatio-temporal dynamics of heterogeneous cancer cell populations and enabled direct monitoring of cells and their descendants in 3D cultures. Besides, novel 3D systems with the advanced mimicking of the in vivo tumor microenvironment are applicable to study different cancer biology phenotypes, particularly drug-resistant and aggressive ones. They are also suitable for investigating new anticancer treatment modalities. The ultimate goal of using phenotype-driven 3D cultures for the investigation of patient biopsies as the most appropriate in vivo mimicking model, can be achieved in the near future.

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Role of apurinic/apyrimidinic nucleases in the regulation of homologous recombination in myeloma: mechanisms and translational significance

Cited by 45 publications

References 52 publications

Integrated genomics and comprehensive validation reveal novel drivers of genomic evolution in esophageal adenocarcinoma

Integrated genomics and comprehensive validation reveal novel drivers of genomic evolution in esophageal adenocarcinoma

Genomic alterations and abnormal expression of APE2 in multiple cancers

Advanced technological tools to study multidrug resistance in cancer

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