Biology subjects

Kumar, M.

Publications and source records attributed to Kumar, M..

At least 145 records · Page 8Linked to original sources

bioRxiv2021

Effective Therapy Targeting Cytochrome bc1 Prevents Babesia Erythrocytic Development and Protects from Lethal Infection

Targeting conserved metabolic processes that are essential for viability of pathogens, such as Plasmodium and Babesia that cause blood-borne diseases, is an effective strategy to eliminate malaria and babesiosis infections with no recrudescence. One interesting target is the mitochondrial cytochrome bc1 complex, which could be inhibited by drugs such as endochin-like quinolones (ELQ) and atovaquone. We used the tick-transmitted and culturable blood-borne pathogen Babesia duncani to evaluate the structure-activity relationship, safety, efficacy and mode of action of ELQs. We identified a potent and highly selective ELQ prodrug (ELQ-502), which alone or in combination with atovaquone eliminates B. microti and B. duncani infections in vitro and in mouse models of parasitemia and lethal infection. The strong efficacy at low dose, excellent safety, bioavailability and long half-life of this experimental therapy makes it an ideal clinical candidate for the treatment of human infections caused by Babesia and its closely related apicomplexan parasites.

microbiology↗

bioRxiv2021

The Sugar Porter gene family of Piriformospora indica: Nomenclature, Transcript Profiling and Characterization

Piriformospora indica is one of the prominent mutualistic root endophyte known to overcome phosphate and nitrogen limitation in a wide variety of plant species, reciprocally takes up carbohydrates for its survival and growth. A total of nineteen potential hexose transporters have been identified from P. indica genome, that may contributes to its potential of carbohydrate assimilation from host plant. Phylogenetic analysis assembles it in 10 groups within 3 clusters. To ease the study, systematic nomenclature were provided to 19 putative hexose transporters as "PiST1-PiST19" in accordance to their appearance on the supercontigs genome sequence of P. indica. The protein length ranges from 487 to 608 amino acids. Out of 19 putative hexose transporters, 9 have been predicted to contain 12 transmembrane domains (PiST1, PiST2, PiST5, PiST6, PiST9, PiST10, PiST11, PiST12 and PiST17), along with MFS family and Sugar porter subfamily motif. Therefore, transcripts were detected for these 9 genes. During colonization, three P. indica genes PiST1, PiST5 and PiST9 have shown induction as compared to axenic culture. Similarly during phosphate starvation, revealed PiST12 to be strongly enhanced. Carbon starvation study in liquid axenic culture resulted in induction of 4 genes, PiST6, PiST9, PiST12 and PiST17. We found co-relation in the expression pattern of PiPT and PiST12 during phosphate starvation. In silico analysis revealed the presence of functional conserved fucose permease (FucP) domain, involved in fructose transport. Phylogenetic analysis revealed that PiST12 groups closely with basidiomycetes hexose transporters. Further, functional complementation of {Delta}hxt null mutant revealed, PiST12 is able to complement growth on fructose and galactose but negligible on glucose.

plant biology↗

bioRxiv2021

Neuroprotective derivatives of tacrine that target NMDA receptor and acetyl cholinesterase - Design, synthesis and biological evaluation

The complex and multifactorial nature of neuropsychiatric diseases demands multi-target drugs that can intervene with various sub-pathologies underlying disease progression. Targeting the impairments in cholinergic and glutamatergic neurotransmissions with small molecules has been suggested as one of the potential disease-modifying approaches for Alzheimers disease (AD). Tacrine, apotent inhibitor of acetylcholinesterase (AChE) is the first FDA approved drug for the treatment of AD. Tacrine is also a low affinity antagonist of N-methyl-D-aspartate receptor (NMDAR). However, tacrine was withdrawn from its clinical use later due to its hepato-toxicity. With an aim to develop novel high affinity multi-target directed ligands (MTDLs) against AChE and NMDAR, with reduced hepatotoxicity, we performed in silico structure-based modifications on tacrine, chemical synthesis of the derivatives and in vitro validation of their activities. Nineteen such derivatives showed inhibition with IC50 values in the range of 18.53{+/-}2.09 to 184.09{+/-}19.23 nM against AChE and 0.27{+/-}0.05 to 38.84{+/-}9.64 M against NMDAR. Some of the selected compounds also protected rat primary cortical neurons from glutamate induced excitotoxicity. Two of the tacrine derived MTDLs, 201 and 208 exhibited in vivo efficacy in rats by protecting against behavioral impairment induced by administration of the excitotoxic agent, monosodium glutamate. Additionally, several of these synthesized compounds also exhibited promising inhibitory activities against butyrylcholinesterase and {beta}-secretase. Given the therapeutic potential of MTDLs in disease-modifying therapy, our studies revealed several promising MTDLs of which 201 appears to be a potential candidate for immediate preclinical and clinical evaluations.

neuroscience↗

bioRxiv2021

Targeting the artemisinin resistant malaria by repositioning of the anti-Hepatitis C Virus drug Alisporivir

The rapid emergence of P. falciparum-resistant strains raises an urgent need to find new antimalarial drug candidates. This study reports the rational repositioning of the anti-Hepatitis C Virus drug, Alisporivir, a non-immunosuppressive analog of cyclosporin A (CsA) against multiple, drug-resistant strains of P. falciparum. Alisporivir being non-hemolytic has been proven to be a better drug than CsA. Indeed, our study also demonstrated the same. Alisporivir inhibited chloroquine-sensitive parasite growth with an IC50 of 196.6nM. Alisporivir also inhibited the growth of chloroquine-resistant parasites with an IC50 of 422.1nM. Alisporivir exhibited, anti-malarial activity in in vivo. Further, we exploited the Cyclophilins targeting potential of Alisporivir against artemisinin-resistant malaria parasite owing to the fact that PfCyP-19B is one of the genes that is overexpressed in artemisinin-resistant parasite revealed by a population transcriptomic study. Our semiquantitative real-time transcript and immunofluorescence analysis confirmed the overexpression of PfCyP-19B in Artemisinin-resistant P. falciparum (PfKelch13R539T). Artemisinin resistance is attributed to slow clearance of ring stage parasites. Ring survival assay (RSA) is designed to access the potency of compounds on these dormant slow clearing parasites leading to drug resistance. Thus, the potency of Alisporivir against PfKelch13R539T was evaluated by RSA. A 2.5-fold decrease in parasite survival was detected with Alisporivir. Further, combination of Alisporivir with DHA found to potentiate the efficacy of DHA by 4.55-fold. These results support the hypothesis that targeting of resistance mechanism is a potential approach to deal with resistant parasite. Overall, this study demonstrates the rational reposition of Alisporivir against resistant malaria resistance.

microbiology↗

bioRxiv2020

Neuroinvasion and encephalitis following intranasal inoculation of SARS-CoV-2 in K18-hACE2 mice

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection can cause neurological disease in humans, but little is known about the pathogenesis of SARS-CoV-2 infection in the central nervous system. Herein, using K18-hACE2 mice, we demonstrate that SARS-CoV-2 neuroinvasion and encephalitis is associated with mortality in these mice. Intranasal infection of K18-hACE2 mice with 105 plaque-forming units of SARS-CoV-2 resulted in 100% mortality by day 6 after infection. The highest virus titers in the lungs were observed at day 3 and declined at days 5 and 6 after infection. In contrast, very high levels of infectious virus were uniformly detected in the brains of all the animals at days 5 and 6. Onset of severe disease in infected mice correlated with peak viral levels in the brain. SARS-CoV-2-infected mice exhibited encephalitis hallmarks characterized by production of cytokines and chemokines, leukocyte infiltration, hemorrhage and neuronal cell death. SARS-CoV-2 was also found to productively infect cells within the nasal turbinate, eye and olfactory bulb, suggesting SARS-CoV-2 entry into the brain by this route after intranasal infection. Our data indicate that direct infection of CNS cells together with the induced inflammatory response in the brain resulted in the severe disease observed in SARS-CoV-2-infected K18-hACE2 mice.

microbiology↗

bioRxiv2020

A Novel Class of Azoles with potent Anti-Leishmanial activity

ObjectivesTo investigate the anti-leishmanial activity of novel azole compounds against Leishmania donovani, which causes deadly visceral leishmaniasis disease. MethodsA focused azole-based library was screened both against promastigotes and amastigotes forms of L. donovani strains in flat-bottomed 96-well tissue-culture plates and J774A.1 macrophages infected with L. donovani. The comprehensive screening azole-based library against L. donovani strains provided novel hits, which can serve as a good starting point to initiate hit to lead optimization campaign. ResultsHits identified from azole-based library exhibited potent in vitro activity against promastigotes and amastigotes of L. donovani. ConclusionsThese potent novel azole hits could be a good starting point to carry out for further medicinal chemistry exploration for anti-leishmania program.

microbiology↗

bioRxiv2020

The N300: An Index For Predictive Coding Of Complex Visual Objects and Scenes

Predictive coding models can simulate known perceptual or neuronal phenomena, but there have been fewer attempts to identify a reliable neural signature of predictive coding for complex stimuli. In a pair of studies, we test whether the N300 component of the event-related potential, occurring 250-350 ms post-stimulus-onset, has the response properties expected for such a signature of perceptual hypothesis testing at the level of whole objects and scenes. We show that N300 amplitudes are smaller to representative ("good exemplars") compared to less representative ("bad exemplars") items from natural scene categories. Integrating these results with patterns observed for objects, we establish that, across a variety of visual stimuli, the N300 is responsive to statistical regularity, or the degree to which the input is "expected" (either explicitly or implicitly) based on prior knowledge, with statistically regular images evoking a reduced response. Moreover, we show that the measure exhibits context-dependency; that is, we find the N300 sensitivity to category representativeness when stimuli are congruent with, but not when they are incongruent with, a category pre-cue. Thus, we argue that the N300 is the best candidate to date for an index of perceptual hypotheses testing for complex visual objects and scenes.

neuroscience↗

bioRxiv2020

Neural crest-derived neurons are replaced by a newly identified mesodermal lineage in the post-natal and aging enteric nervous system

The enteric nervous system (ENS), a collection of neural cells contained in the wall of the gut, is of fundamental importance to gastrointestinal and systemic health. According to the prevailing paradigm, the ENS arises from progenitor cells migrating from the neural crest and remains largely unchanged thereafter. Here, we show that the lineage composition of maturing ENS changes with time, with a decline in the canonical lineage of neural-crest derived neurons and their replacement by a newly identified lineage of mesoderm-derived neurons. Single cell transcriptomics and immunochemical approaches establish a distinct expression profile of mesoderm-derived neurons. The dynamic balance between the proportions of neurons from these two different lineages in the post-natal gut is dependent on the availability of their respective trophic signals, GDNF-RET and HGF-MET. With increasing age, the mesoderm-derived neurons become the dominant form of neurons in the ENS, a change associated with significant functional effects on intestinal motility which can be reversed by GDNF supplementation. Transcriptomic analyses of human gut tissues show reduced GDNF-RET signaling in patients with intestinal dysmotility which is associated with reduction in neural crest-derived neuronal markers and concomitant increase in transcriptional patterns specific to mesoderm-derived neurons. Normal intestinal function in the adult gastrointestinal tract therefore appears to require an optimal balance between these two distinct lineages within the ENS.

neuroscience↗

bioRxiv2020

RNA binding of Hfq monomers promotes RelA-mediated hexamerization in a limiting Hfq environment

The RNA chaperone Hfq acting as a hexamer, is a known mediator of post-transcriptional regulation expediting basepairing between small RNAs (sRNAs) and their target mRNAs. However, the intricate details associated with Hfq-RNA biogenesis are still unclear. Previously, we reported that the stringent response regulator, RelA is a functional partner of Hfq that facilitates Hfq-mediated sRNA-mRNA regulation in vivo and induces Hfq hexamerization in vitro. Here, for the first time we show that RelA-mediated Hfq hexamerization requires an initial binding of RNA, preferably sRNA to Hfq monomers. By interacting with a Shine-Dalgarno-like sequence (GGAG) in the sRNA, RelA stabilizes the initially unstable complex of RNA bound-Hfq monomer, enabling the attachment of more Hfq subunits to form a functional hexamer. Overall, our study showing that RNA binding to Hfq monomers is at the heart of RelA-mediated Hfq hexamerization, challenges the previous concept that only Hfq hexamers can bind RNA.

microbiology↗

bioRxiv2020

ADEP1 activated ClpP1P2 macromolecule of Leptospira, an ideal Achilles' heel to deregulate proteostasis and hamper the cell survival

The caseinolytic protease (ClpP) complex in Leptospira interrogans is unusual in its functional activation. The genus Leptospira has two ClpPs, ClpP1 and ClpP2, which transcribes independently, regardless it couples to form the active tetradecamer. Acyldepsipeptide (ADEP) antibiotic hampers the growth of numerous bacterial species by activating the target protein ClpP and dysregulating the physiological proteostasis within the cell. In vitro culture of the L. interrogans fortified with the ADEP impeded the spirochete growth accompanied by a more elongated morphology. The chemoactivation of the ClpP is conditional on the duration of the self-compartmentalization of each of the ClpP isoforms. The small extent (10 min) self-assembled ClpP1P2 revealed inhibition in the peptidase activity (7-fold) in the presence of the ADEP due to the self-cleavage of the ClpP subunits. On supplementation of the {beta}-casein or bovine serum albumin, the peptidase activity of the ClpP1P2 (short-incubated) got enhanced by the ADEP, while the ClpP1P2 (long-incubated) activity was retained to the same level. ADEP can also switch on the ClpP1P2 from a strict peptidase into proteolytic machinery that discerns and degrades the unfolded protein substrates autonomous of the cognate chaperone ClpX. In consensus to the most prokaryotes with the multi ClpP variants, the computational prototype of the ClpP1P2 tertiary structure infers that the hydrophobic pocket wherein the ADEPs predominantly docks are present in the ClpP2 heptamer. Additionally, the dynamic light scattering and the site-directed mutagenesis of a catalytic serine residue in either of the ClpP isoforms proposes a second interaction site for the ADEP.

microbiology↗

bioRxiv2020

Molecular Determinants of Prognosis and Evolution in Diffuse-Lower Grade Astrocytomas

Low grade astrocytomas (LGAs) are classified based on the mutational status of the isocitrate dehydrogenase (IDH) gene. While IDH wild-type (WT) LGAs evolve rapidly to glioblastoma, mutant tumors generally have a more indolent course. To identify potential drivers of the differential progression of LGAs, we analyzed transcriptomes from The Cancer Genome Atlas. Compared to mutant LGAs, platelet-derived growth factor (PDGF) signaling is enriched in WT cases, and PDGFA is the top overexpressed gene in the pathway. Putative mechanisms for differential PDGFA expression included copy number gains of chromosome 7 in WT cases and methylation of the PDGFA promoter in mutant LGAs. Additionally, we found that high PDGFA expression is associated with aneuploidy, immunosuppressive features, and worse prognosis, and that WT LGAs use multiple means to inactivate the p53 pathway to progress to GBM. Our work highlights the contribution of PDGF gene family towards the unique behaviour of LGAs. STATEMENT OF SIGNIFICANCEThis study of gene expression in LGAs suggests that differential regulation of the PDGF pathway may underlie the different natural histories of IDH WT and IDH mutant LGAs including divergent evolutionary trajectories to GBM. This insight may inspire new therapeutic strategies to suppress the transformation of LGAs to higher-grade cancers.

cancer biology↗

bioRxiv2020

An atlas of Arabidopsis protein S-Acylation reveals its widespread role in plant cell organisation of and function.

S-acylation is the addition of a fatty acid to a cysteine residue of a protein. While this modification may profoundly alter protein behaviour, its effects on the function of plant proteins remains poorly characterised, largely as a result to the lack of basic information regarding which proteins are S-acylated and where in the proteins the modification occurs. In order to address this gap in our knowledge, we have performed a comprehensive analysis of plant protein S-acylation from 6 separate tissues. In our highest confidence group, we identified 5185 cysteines modified by S-acylation, which were located in 4891 unique peptides from 2643 different proteins. This represents around 9% of the entire Arabidopsis proteome and suggests an important role for S-acylation in many essential cellular functions including trafficking, signalling and metabolism. To illustrate the potential of this dataset, we focus on cellulose synthesis and confirm for the first time the S-acylation of all proteins known to be involved in cellulose synthesis and trafficking of the cellulose synthase complex. In the secondary cell walls, cellulose synthesis requires three different catalytic subunits (CESA4, CESA7 and CESA8) that all exhibit striking sequence similarity. While all three proteins have been widely predicted to possess a RING-type zinc finger at their N-terminus, for CESA4 and CESA8, we find evidence for S-acylation of cysteines in this region that is incompatible with any role in coordinating metal ions. We show that while CESA7 may possess a RING type domain, the same region of CESA4 and CESA8 appear to have evolved a very different structure. Together, the data suggests this study represents an atlas of S-acylation in Arabidopsis that will facilitate the broader study of this elusive post-translational modification in plants as well as demonstrates the importance of undertaking further work in this area.

plant biology↗

bioRxiv2020

Abundance and diversity of phages, microbial taxa and antibiotic resistance genes in the sediments of the river Ganges through metagenomic approach

In the present study, we have analyzed the metagenomic DNA from the pooled sediment sample of the river Ganges to explore the abundance and diversity of phages, microbial community and antibiotic resistance genes. Utilizing data from Illumina platform, 4174 ([~]0.0013%) reads were classified for the 285 different DNA viruses largely dominated by the group of 260 distinctive phages (3602 reads, [~]86.3%). Among all, Microcystis (782 hits), Haemophilus (403), Synechococcus (386), Pseudomonas (279), Enterococcus (232), Bacillus (196), Rhodococcus (166), Caulobacter (163), Salmonella (146), Enterobacteria (143), Mycobacterium (128), Propionibacterium (71), Erwinia (70), Ralstonia (56) phages shows the highest abundance and account for approximately 90% of the total identified phages. Additionally, we have also identified corresponding host pertaining to these phages. Mainly, Proteobacteria ([~]69.3%) dominates the microbial population structure. Primarily orders such as Caulobacterales ([~]28%), Burkholderiales ([~]13.9%), Actinomycetales ([~]13.7%), Pseudomonadales ([~]7.5%) signify the core section. Further, 21869 ([~]0.00695%) reads were classified in 20 ARG types (classes) and 240 ARGs (subtypes) among which 4 ARG types namely multidrug resistance (MDR) (12041 reads, [~]55%), bacitracin (3202 reads, [~]15%), macrolide-lincosamide-streptogramin (MLS) (1744 reads, [~]7.98%), and fosmidomycin (990 reads, [~]4.53%) has the highest abundance. Simultaneously, six resistance mechanisms were also recognized with the dominance of antibiotic efflux (72.8%, 15919 reads). The results unveil the distribution of (pro)-phages; microbial community and various ARGs in the Ganges river sediments. Further research on these identified phage(s) could be used in phage-based therapeutics against pathogenic bacteria.

genomics↗

bioRxiv2020

The FDA-approved gold drug Auranofin inhibits novel coronavirus (SARS-COV-2) replication and attenuates inflammation in human cells

SARS-COV-2 has recently emerged as a new public health threat. Herein, we report that the FDA-approved gold drug, auranofin, inhibits SARS-COV-2 replication in human cells at low micro molar concentration. Treatment of cells with auranofin resulted in a 95% reduction in the viral RNA at 48 hours after infection. Auranofin treatment dramatically reduced the expression of SARS-COV-2-induced cytokines in human cells. These data indicate that auranofin could be a useful drug to limit SARS-CoV-2 infection and associated lung injury due to its anti-viral, anti-inflammatory and anti-ROS properties. Auranofin has a well-known toxicity profile and is considered safe for human use.

microbiology↗

bioRxiv2020

CREBBP/EP300 mutation is associated with poor outcome in HNSCC and targetable with synthetic cytotoxicity.

Despite radiation forming the curative backbone of over 50% of malignancies, there are no genomically-driven radiation sensitizers for clinical use. We performed in vivo shRNA screening to identify targets generally associated with radiation response as well as those exhibiting a genomic dependency. This identified the histone acetyltransferases CREBBP/EP300 as a target for radiosensitization in combination with radiation in cognate mutant tumors. Further in vitro and in vivo studies confirmed this phenomenon was due to repression of homologous recombination following DNA damage and can be reproduced using chemical inhibition of histone acetyltransferase (HAT), but not bromodomain function. Selected mutations in CREBBP lead to a hyperacetylated state that increases CBP and BRCA1 acetylation, representing a gain of function targets by HAT inhibition. Additionally, mutations in CREBBP/EP300 were associated with recurrence following radiation, in several squamous cell carcinoma cohorts. These findings represent both a novel mechanism of treatment resistance and the potential for genomically-driven treatment.

cancer biology↗

bioRxiv2020

Rapid, field-deployable nucleobase detection and identification using FnCas9

Detection of pathogenic sequences or variants in DNA and RNA through a point-of-care diagnostic approach is valuable for rapid clinical prognosis. In recent times, CRISPR based detection of nucleic acids has provided an economical and quicker alternative to sequencing-based platforms which are often difficult to implement in the field. Here, we present FnCas9 Editor Linked Uniform Detection Assay (FELUDA) that employs a highly accurate enzymatic readout for detecting nucleotide sequences, identifying nucleobase identity and inferring zygosity with precision. We demonstrate that FELUDA output can be adapted to multiple signal detection platforms and can be quickly designed and deployed for versatile applications including rapid diagnosis during infectious disease outbreaks like COVID-19.

molecular biology↗

bioRxiv2020

Adhatoda Vasica ameliorates cellular hypoxia dependent mitochondrial dysfunction in acute and severe asthmatic mice.

Severe asthma is a chronic airway disease that exhibits poor response to conventional asthma therapies. Growing evidence suggests that elevated hypoxia increases the severity of asthmatic inflammation among patients and in model systems. In this study, we elucidate the therapeutic effects and mechanistic basis of Adhatoda Vasica (AV) aqueous extract on mouse models of acute allergic as well as severe asthma subtypes at physiological, histopathological, and molecular levels. Oral administration of AV extract attenuates the increased airway resistance and inflammation in acute allergic asthmatic mice and alleviates the molecular signatures of steroid (dexamethasone) resistance like IL-17A, KC, and HIF-1 (hypoxia inducible factor-1alpha) in severe asthmatic mice. AV inhibits HIF-1 levels through restoration of expression of its negative regulator-PHD2 (prolyl hydroxylase domain-2). Alleviation of hypoxic response mediated by AV is further confirmed in the acute and severe asthma model. AV reverses cellular hypoxia-induced mitochondrial dysfunction in human bronchial epithelial cells - evident from bioenergetic profiles and morphological analysis of mitochondria. In silico docking of AV constituents reveal higher negative binding affinity for C and O-glycosides for HIF-1, IL-6, Janus kinase 1/3, TNF- and TGF-{beta}-key players of hypoxia-inflammation. This study for the first time provides a molecular basis of action and effect of AV whole extract that is widely used in Ayurveda practice for diverse respiratory ailments. Further, through its effect on hypoxia-induced mitochondrial dysfunction, the study highlights its potential to treat severe steroid-resistant asthma. Significance StatementSevere asthma is a global health concern with a large fraction unresponsive to current treatment modalities involving corticosteroids. Recent findings suggest that elevated hypoxia has a critical role in severity of asthma. Here, we report therapeutic treatment with aqueous extract of Adhatoda Vasica (AV), an ayurvedic medicine, attenuates sever steroid insensitive asthmatic features in mice. The observed effects of AV are through inhibition of hypoxic response, both in vivo and in vitro. AV also reverses mitochondrial dysfunction, a key consequence associated with hypoxia, and asthma. This study highlights the translational potential of AV for the treatment of severe asthma and provides opportunities for its usage in other disease conditions where hypoxia is pertinent.

immunology↗

bioRxiv2020

ATM-deficient lung, prostate and pancreatic cancer cells are acutely sensitive to the combination of olaparib and the ATR inhibitor AZD6738

BackgroundThe ataxia telangiectasia mutated (ATM) protein kinase is mutated in several human cancers, presenting potential opportunities for targeted cancer therapy. We previously reported that the poly-ADP ribose polymerase (PARP) inhibitor olaparib induced transient G2 arrest but not cell death in ATM-deficient A549 lung cancer cells, while the combination of olaparib with the ATM-, Rad3-related (ATR) inhibitor VE-821 induced cell death. Here, we show that the clinically relevant ATR inhibitor, AZD6738, sensitizes ATM-deficient A549 lung, prostate and pancreatic cancer cells to olaparib. MethodsATM was depleted from A549 lung cancer cells, PC-3 prostate cancer cells and Panc 10.05 pancreatic cancer cells, and the effects of olaparib alone and in combination with AZD6738 were determined. ResultsThe combination of olaparib plus AZD6738 induced cell death in ATM-deficient lung, prostate and pancreatic cancer cells with little effect on their ATM-proficient counterparts. ConclusionsLung, prostate and pancreatic patients whose tumours exhibit loss or inactivation of ATM may benefit from combination of a PARP inhibitor plus an ATR inhibitor.

cancer biology↗