Biology subjects

Lord, C. J.

Publications and source records attributed to Lord, C. J..

18 recordsLinked to original sources

bioRxiv2026

Global signatures of Ribonucleotide Excision Repair deficiency and its therapeutic vulnerabilities

Cancer therapies increasingly exploit DNA repair deficiencies, yet many clinically actionable repair-deficient states remain undetectable because they lack robust biomarkers and are not identifiable through gene-based diagnostics. Here, we show that deficiency of ribonucleotide excision repair (RER), a pathway that removes misincorporated ribonucleotides from genomic DNA, generates a distinct genome-wide mutational phenotype comprising characteristic insertion-deletion, substitution, and structural variation signatures. Using these features, we developed RERDetect, a whole-genome classifier that identifies RER-deficient tumors across diverse cancer types. Application of RERDetect to more than 11,000 primary and metastatic cancers revealed a recurrent subset of tumors with evidence of RER deficiency, the majority lacking detectable genetic alterations in RNASEH2 genes. We identified promoter hypermethylation of RNASEH2C as a recurrent mechanism of pathway inactivation. RER-deficient cells exhibited distinct vulnerabilities, including sensitivity to EXO1 and FANCM inhibition. These findings establish RER deficiency as a previously unrecognized and therapeutically actionable DNA repair-deficient state in cancer, demonstrating the power of mutational scars to identify clinically relevant tumor phenotypes that evade conventional genomic diagnostics.

genomics↗

bioRxiv2026

Predicting resistance to synthetic lethal therapies in cancer

Background Synthetic lethality (SL) occurs when an alteration in one gene renders cells vulnerable to inhibition of another, offering a strategy for targeted cancer therapy. PARP inhibitors represent the first clinically approved synthetic lethal therapy, and numerous additional candidates are now in clinical trials. Unfortunately, resistance to these therapies is common and impairs their overall effectiveness. Although there is a growing understanding of the factors that predict synthetic lethal interactions, the prediction of mechanisms driving resistance to these effects remains largely unstudied. Here, we sought to determine whether SL resistance could be predicted a priori using protein-protein interaction networks integrated with additional molecular profiles. Methods We curated genome-wide CRISPR-Cas9 chemogenetic resistance screens spanning ten unique SL biomarker-target pairs. For each pair, we extracted resistance genes and computed features capturing protein-protein interactions, gene expression, and essentiality. We compared these features between resistance and non-resistance genes and developed a random forest classifier to predict resistance. Model performance was assessed using random-split and structured leave-one-out schemes based on biomarkers, targets, and SL pairs to ensure robust generalisation. Independent validation of the model was performed by assessing its ability to predict resistance to two SL therapies currently in clinical trials, MTAP-PRMT5 and ATM-ATR. Results Resistance genes were significantly enriched among the protein-protein interaction partners of SL pairs across multiple datasets, suggesting functional interaction networks can aid the prioritisation of resistance mechanisms. Resistance genes tended to be more co-expressed with their associated target and also displayed distinct essentiality patterns. Although no individual feature was strongly predictive, integrating all features in a random forest model improved discrimination between resistance and non-resistance genes. Under leave-one-SL-pair-out cross-validation - our most stringent test of generalisation - the model achieved a mean area under the receiver operating characteristic curve (AUROC) of 0.72 across ten pairs (range 0.57-0.91; mean average precision ~9%); a random train-test split gave a higher AUROC (~0.78) that we treat as an optimistic upper bound, since biomarkers and targets are shared across folds. Average precision remained low in absolute terms, reflecting the inherent challenge of predicting extremely rare resistance events (<1% of genes). Conclusions Resistance to synthetic lethal therapies arises, at least in part, from predictable patterns of network connectivity, transcriptional coordination, and context-dependent essentiality. Our integrative framework provides a computational approach for anticipating resistance mechanisms across the expanding landscape of synthetic lethal therapies, offering a foundation for designing more durable and effective combination treatments.

cancer biology↗

bioRxiv2026

Mutational and functional heterogeneity of homology-directed repair deficiency and clinical implications

Homology-directed repair deficiency (HRd) encompasses mutations in multiple genes yet is treated clinically as a single entity. Here, through parallel analyses of isogenic knockouts of multiple HR pathway genes, integrating multi-omic analyses with genome-wide CRISPR-Cas9-dependency and resistance screens, we show that HRd is not a single entity but exists along a molecular and functional continuum. BRCA1, BRCA2, PALB2, RAD51C, and RAD51D mutants shared many HRd-associated mutational signatures, while RAD51B, BRIP1, CDK12 exhibited distinct genomic patterns. Functional heterogeneity was equally apparent: synthetic lethal interactions including CIP2A and a novel dependency on PRDX1 were penetrant across most HRd genotypes, whereas FANCM dependency was linked to HRd subtypes characterized by tandem duplications. PARPi resistance screens in distinct HRd contexts uncovered BRIP1 and RECQL5 as new BRCA2-specific resistance genes. HRd is thus a complex continuum, underscoring why modernizing the molecular taxonomy utilizing all genomic features available per patient is crucial to informing precision interventions.

genomics↗

bioRxiv2026

Reversion mutations define minimal BRCA1/2 requirements for therapy resistance

Although platinum salts or PARP inhibitors are effective in delivering anti-tumor responses in people with BRCA1 or BRCA2 mutated cancers, drug resistance is common and is often caused by secondary BRCA1/2 reversion mutations that restore function. By collating and analyzing 848 BRCA1/2 reversion mutations in 384 cancer patients with drug resistance, we confirm that pathogenic BRCA1/2 mutation type influences the acquisition of reversions, and that large BRCA1/2 deletions are an underappreciated form of reversion. Integrating reversion data with systematic CRISPR-Cas9 screens that delete BRCA1/2 exons, we also show that both proteins contain privileged domains whose structure is essential for drug resistance, including the PALB2 interacting domains of both BRCA1 and BRCA2. Reversions in PALB2 also conserve both BRCA1 and BRCA2 binding domains. Surprisingly, exon 11 of BRCA2, which encodes BRC repeats 1-8, is not essential for resistance. Using this patient and functional information, we estimate the likelihood of pathogenic BRCA2 mutations to revert. We show that risk of reversion correlates with both the presence of clinical reversions and the response to treatment, suggesting that the propensity to revert could be a useful clinical parameter.

cancer biology↗

bioRxiv2026

The FANCM-RMI1/2 complex promotes genomic instability and PARP inhibitor sensitivity in BRCA2-deficicient cells.

Cancer cells lacking BRCA1 or BRCA2 must adapt to survive and proliferate despite defective DNA repair and high genomic instability. Restoration of homologous recombination (HR) through loss of DNA end protection rescues growth defects and promotes PARP inhibitor (PARPi) resistance in BRCA1-deficient cells; however, the genetic basis of adaptation to BRCA2 loss remains largely unexplored. To delineate BRCA1- and BRCA2-specific adaptation trajectories, we established a fully isogenic screening platform in mouse embryonic stem cells engineered for acute depletion of either protein. This approach uncovered hundreds of genes with shared, distinct, or even opposing effects between the two BRCA-deficiency states. We identified FANCM and its interacting partners RMI1/2, CENPS/MHF1, CENPX/MHF2, and FAAP24 as essential in BRCA1-deficient cells but toxic in BRCA2-deficient contexts. Loss of FANCM in BRCA2-deficient cells alleviated genomic instability and proliferation defects by preventing RMI1/2-dependent replication fork degradation, without rescuing HR. Moreover, we show that the FANCM-RMI1/2 complex drives PARPi sensitivity in both mouse and human BRCA2-deficient cells, in contrast to the 53BP1-SHLD-CST axis in BRCA1-deficient cells. These findings reveal distinct adaptation routes to BRCA1 and BRCA2 loss and establish FANCM as a determinant of BRCA2-specific vulnerability and therapeutic response, with direct implications for tailoring prevention and therapy according to BRCA mutation status.

cancer biology↗

bioRxiv2025

Nucleophagy removes cytotoxic trapped PARP1

Poly (ADP-Ribose) Polymerase inhibitors (PARPi) induce cytotoxicity in homologous recombination repair (HRR)-deficient cancers by causing PARP1 to become trapped on chromatin, resulting in irreparable replication-associated DNA damage. Although increased clearance of trapped PARP1 from chromatin reduces the sensitivity of cancer cells to PARPi, details surrounding this process remain unclear. PARPi exposure is known to cause increased autophagy flux, whilst autophagy inhibition can hypersensitise cells to PARPi. Using various biochemical, cell biological and live imaging-based assays, we found that trapped PARP1 is cleared by nucleophagy, the selective autophagy of nuclear substrates. Specifically, the nucleophagy of trapped PARP1 was orchestrated by the selective autophagy receptor TEX264 and its partner segregase p97/VCP. TEX264 mediates this process by directly interacting with trapped PARP1, thus bridging PARP1 to the autophagosomal resident protein LC3 for processing via autophagy. Impeding this process, either chemically or genetically, heightened PARP1 trapping, leading to accumulation of protein aggregates, replication-associated DNA damage and cell lethality, re-sensitising PARPi-resistant cells to various PARPi. In conclusion, we show that nucleophagy acts in a cytoprotective manner to directly target PARPi-induced trapped PARP1 for degradation.

cell biology↗

bioRxiv2025

LOX inhibition disrupts a collagen-integrin-MYC axis as a translatable targeting strategy in invasive lobular carcinoma

Invasive lobular carcinoma (ILC) accounts for 15% of breast cancers yet lacks specific therapy because ILCs are underrepresented in clinical trials and preclinical models are lacking. We established intraductal xenograft models to test whether the clinical pan-lysyl-oxidase PXS-5505, now in phase trials for myelofibrosis can exploit the collagen-rich matrix dependency created by CDH1 loss. PXS-5505 remodels fibrillar collagen, and halts tumor expansion and metastatic seeding across ER+ and triple negative models without systemic toxicity. Genome-wide CRISPR screens reveal ITGAV and ITGB5 as synthetic lethal partners of CDH1 and LOX inhibition downregulates their expression together with MYC, NF-{kappa}B, and AP-1 transcriptional programmes. Collagen fibre density/alignment, and MYC/AP-1 gene signatures serve as pharmacodynamic readouts of drug activity. These data uncover a tractable ECM-integrin-MYC axis in ILC and nominate PXS-5505, alone or with endocrine therapy, for window of opportunity trials in this understudied breast cancer subtype. One Sentence SummaryTargeting matrix remodelling in ILC inhibits ILC progression and alters multiple molecular endpoints, providing a translatable therapeutic strategy for this understudied subtype that requires better treatments.

cancer biology↗

bioRxiv2025

Targeting non-canonical NF-κB signalling in CYLD cutaneous syndrome by selective inhibition of IκB kinase alpha.

CYLD cutaneous syndrome (CCS) skin tumors develop from puberty onwards, can number in the hundreds and progressively grow over time. CCS patients lack medical therapies and require repeated surgery to control tumor burden. CYLD loss of heterozygosity (LOH) drives tumor growth, and CCS tumors have previously been shown to demonstrate increased canonical NF-{kappa}B and Wnt signalling. Here, we demonstrate evidence of non-canonical NF-{kappa}B signalling in CCS tumor keratinocytes, with increased p100 to p52 processing and RelB protein expression compared to normal skin. Utilizing complementary transcriptomics and proteomics on patient derived CCS tumor cell fractions, we identify I{kappa}B kinase alpha (IKK) as a candidate target in the non-canonical NF-{kappa}B signalling pathway. A novel, highly selective, IKK inhibitor (SU1644) used in patient derived CCS tumor spheroid cultures demonstrated that IKK inhibition reduced tumor spheroid viability. These data provide the pre-clinical rationale for the assessment of topical IKK inhibitors as a novel preventative treatment for CCS. TeaserTopical IKK inhibition emerges as a potential therapy for CYLD cutaneous syndrome by targeting non-canonical NF-{kappa}B signalling Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=125 SRC="FIGDIR/small/635629v1_ufig1.gif" ALT="Figure 1"> View larger version (39K): org.highwire.dtl.DTLVardef@829218org.highwire.dtl.DTLVardef@459f5dorg.highwire.dtl.DTLVardef@e198f6org.highwire.dtl.DTLVardef@1015685_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2024

Sequential ATR and PARP Inhibition Overcomes Acquired DNA Damaging Agent Resistance in Pancreatic Ductal Adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) remains the most lethal cancer and will soon be the second most common cause of cancer related death. While regimens containing DNA damaging agents such as FOLFIRINOX and PARP inhibitors have derived clinical benefits for some patients, their efficacy invariably fails over time. This presents a significant clinical challenge, and thus there is an urgent need for novel therapeutic strategies which are able to overcome the acquisition of resistance in PDAC. Clinically relevant models of treatment resistance were generated from patient-derived cell lines by extended exposure to chemotherapy agents. Synergy scoring, clonogenicity assays, flow cytometry, immunofluorescence and transcriptomic analysis were used to investigate the efficacy of combined ATR and PARP inhibition in re-sensitising resistant PDAC to treatment. Acquisition of resistance was associated with transcriptomic shifts in cell cycle checkpoint regulation, metabolic control, DNA damage response (DDR), programmed cell death and the replication stress response. Additionally, combined treatment with the ATR inhibitor (ceralasertib), and the PARP inhibitor (olaparib) was synergistic in all models of acquired resistance. Sequential treatment using ceralasertib prior to olaparib was highly effective at low dose for DDR proficient cell lines, whereas DDR deficient models responded better when treated with olaparib first. We provide in vitro evidence of a novel therapeutic strategy to overcome acquired PARP inhibitor and platinum resistance in PDAC by using sequential exposure to ceralasertib and Olaparib. A sequential regimen may be more tolerable and should be investigated clinically to circumvent dose limiting toxicity in concurrent combinations.

cancer biology↗

bioRxiv2024

CDK12 Loss Promotes Prostate Cancer Development While Exposing Vulnerabilities to Paralog-Based Synthetic Lethality

Biallelic loss of cyclin-dependent kinase 12 (CDK12) defines a unique molecular subtype of metastatic castration-resistant prostate cancer (mCRPC). It remains unclear, however, whether CDK12 loss per se is sufficient to drive prostate cancer development--either alone, or in the context of other genetic alterations--and whether CDK12-mutant tumors exhibit sensitivity to specific pharmacotherapies. Here, we demonstrate that tissue-specific Cdk12 ablation is sufficient to induce preneoplastic lesions and robust T cell infiltration in the mouse prostate. Allograft-based CRISPR screening demonstrated that Cdk12 loss is positively associated with Trp53 inactivation but negatively associated with Pten inactivation--akin to what is observed in human mCRPC. Consistent with this, ablation of Cdk12 in prostate organoids with concurrent Trp53 loss promotes their proliferation and ability to form tumors in mice, while Cdk12 knockout in the Pten-null prostate cancer mouse model abrogates tumor growth. Bigenic Cdk12 and Trp53 loss allografts represent a new syngeneic model for the study of androgen receptor (AR)-positive, luminal prostate cancer. Notably, Cdk12/Trp53 loss prostate tumors are sensitive to immune checkpoint blockade. Cdk12-null organoids (either with or without Trp53 co-ablation) and patient-derived xenografts from tumors with CDK12 inactivation are highly sensitive to inhibition or degradation of its paralog kinase, CDK13. Together, these data identify CDK12 as a bona fide tumor suppressor gene with impact on tumor progression and lends support to paralog-based synthetic lethality as a promising strategy for treating CDK12-mutant mCRPC.

cancer biology↗

bioRxiv2023

PARP inhibitors enhance reovirus-mediated cell killing through the death-inducing signaling complex (DISC) with an associated NF-kappa B-regulated immune response.

Oncolytic Reovirus type 3 Dearing (RT3D), is a naturally occurring double-stranded (ds) RNA virus that is under development as an oncolytic immunotherapy We used an unbiased high-throughput cytotoxicity screen of different targeted therapeutic agents with the aim of identifying potential drug-viral sensitizers to enhance RT3D tumour killing. Talazoparib, a clinical poly(ADP)-ribose polymerase 1 (PARP-1) inhibitor, was identified as a top hit and found to cause profound sensitisation to RT3D. This effect was not seen with other classes of oncolytic virus and was not mediated by enhanced viral replication or PARP inhibitor-related effects on the DNA damage response. RT3D interacts with retinoic acid-induced gene-1 (RIG-I) and activates PARP-1, with consequent PARylation of components of the extrinsic apoptosis pathway. Pharmacological and genetic inhibition of PARP-1 abrogates this PARylation and increases levels of extrinsic apoptosis, NF-kB signalling and pro-inflammatory cell death. Direct interaction between PARP-1 and RIG-I following RT3D/talazoparib treatment is a key factor in activating downstream signaling pathways that lead to IFN-{beta} and TNF-/TRAIL production which, in turn, amplify the therapeutic effect through positive feedback. Critically, it was possible to phenocopy the effect of RT3D through the use of non-viral ds-RNA therapy and RIG-I agonism. In in vivo studies, we demonstrated profound combinatorial efficacy of RT3D and talazoparib in human A375 melanoma in immunodeficient mice. More impressively, in immunocompetent mouse models of 4434 murine melanoma, we achieved 100% tumour control and protection from subsequent tumour rechallenge with the combination regimen. Correlative immunophenotyping confirmed significant innate and adaptive immune activation with the combination of RT3D and PARP inhibition. Taken together, these data provide a clear line of sight to clinical translation of combined regimens of PARP inhibition or ds-RNA agonism, with either viral or non-viral agents, in tumour types beyond the relatively narrow confines of current licensed indications for PARP inhibition.

cancer biology↗

bioRxiv2022

CDK4/6 inhibition and dsRNA sensor agonism co-operate to enhance anti-cancer effects through ER stress and immune modulation of tumour cells

Cytoplasmic pattern recognition receptors (PRRs) for double-stranded RNA (RIG-I/MDA5) are key mediators of anti-viral responses. PRR agonists, such as dsRNA oncolytic Reovirus type 3 Dearing (Rt3D), potently activate RNA sensors. We used an unbiased cytotoxicity screen to reveal synergistic drug-virotherapy combinations and found potent effects of Rt3D combined with the CDK4/6 inhibitor, palbociclib. The combination augmented oncolytic virus-induced endoplasmic reticulum (ER) stress/unfolded protein response (UPR) and the expression and activation/signaling of RNA sensors. Combined Rt3D-palbociclib treatment potently increased interferon production and signaling, and knockdown studies implicated key UPR proteins and the RNA sensor, RIG-I, as essential to the phenotype observed. Further experiments, using canonical RIG-I agonists and an ER stress inducer, thapsigargin, confirmed cross-talk between RNA sensing and ER stress pathways that augmented cancer cell death and interferon production. Combined Rt3D-palbociclib also increased innate immune activation within tumour cells and IFN-induced HLA expression. Analysis of the immunopeptidome revealed changes to HLA-captured peptides with Rt3D-palbociclib, including altered expression of peptides from cancer/testis antigens (CTA) and endogenous retroviral elements (ERVs). Our findings highlight cross-talk between UPR signaling and RNA-mediated PRR activation as a means of enhancing anti-cancer efficacy with potential pro-immunogenic consequences. This has implications for future clinical development of PRR agonists and oncolytic viruses, and broadens the therapeutic remit of CDK4/6 inhibitors to include roles as both ER stress and dsRNA PRR sensitizers.

cancer biology↗

bioRxiv2022

MND1 and PSMC3IP control PARP inhibitor sensitivity in mitotic cells

The PSMC3IP-MND1 heterodimer promotes RAD51 and DMC1-dependent D-loop formation during meiosis in yeast and mammalian organisms. For this purpose, it catalyzes the DNA strand exchange activities of the recombinases. Interestingly, in a panel of genome-scale CRISPR-Cas9 mutagenesis and interference screens in mitotic cells, we found that depletion of either PSMC3IP or MND1 caused sensitivity to clinical Poly (ADP-Ribose) Polymerase inhibitors (PARPi). A retroviral mutagenesis screen in mitotic cells also identified PSMC3IP and MND1 as genetic determinants of ionizing radiation sensitivity. The role PSMC3IP and MND1 play in preventing PARPi sensitivity in mitotic cells appears to be independent of a previously described role in alternative lengthening of telomeres (ALT). PSMC3IP or MND1 depleted cells accumulate toxic RAD51 foci in response to DNA damage, show impaired homology-directed DNA repair, and become PARPi sensitive, even in cells lacking both BRCA1 and TP53BP1. Although replication fork reversal is also affected, the epistatic relationship between PSMC3IP-MND1 and BRCA1/BRCA2 suggests that the abrogated D-loop formation is the major cause of PARPi sensitivity. This is corroborated by the fact that a PSMC3IP p.Glu201del D-loop formation mutant associated with ovarian dysgenesis fails to reverse PARPi sensitivity. These observations suggest that meiotic proteins such as MND1 and PSMC3IP could have a greater role in mitotic cells in determining the response to therapeutic DNA damage.

cancer biology↗

bioRxiv2021

The ubiquitin-dependent ATPase p97 removes cytotoxic trapped PARP1 from chromatin

Summary paragraphPoly-(ADP-ribose) polymerase inhibitors (PARPi) elicit anti-tumour activity in homologous recombination defective cancers by promoting cytotoxic, chromatin-bound, "trapped" PARP1. How cells process trapped PARP1 remains unclear. By exploiting wild-type or trapping-resistant PARP1 transgenes combined with either a rapid immunoprecipitation mass-spectrometry of endogenous proteins (RIME)-based approach, or PARP1 Apex2-proximity labelling linked to mass-spectrometry, we generated proteomic profiles of trapped and non-trapped PARP1 complexes. This combined approach identified an interaction between trapped PARP1 and the ubiquitin-regulated p97 ATPase (aka VCP). Subsequent experiments demonstrated that upon trapping, PARP1 is SUMOylated by the SUMO-ligase PIAS4 and subsequently ubiquitinated by the SUMO-targeted E3-ubiquitin ligase, RNF4, events that promote p97 recruitment and p97 ATPase-mediated removal of trapped-PARP1 from chromatin. Consistent with this, small molecule p97 complex inhibitors, including a metabolite of the clinically-used drug disulfiram (CuET) that acts as a p97 sequestration agent, prolong PARP1 trapping and thus enhance PARPi-induced cytotoxicity in homologous recombination-defective tumour cells and patient-derived tumour organoids. Taken together, these results suggest that p97 ATPase plays a key role in the processing of trapped PARP1 from chromatin and the response of homologous recombination defective tumour cells to PARPi.

molecular biology↗

bioRxiv2019

Robust genetic interactions in cancer are enriched in protein-protein interaction pairs

Genetic interactions, such as synthetic lethal effects, can now be systematically identified in cancer cell lines using high-throughput genetic perturbation screens. Despite this advance, few genetic interactions have been reproduced across multiple studies and many appear highly context-specific. Understanding which genetic interactions are robust in the face of the molecular heterogeneity observed in tumours and what factors influence this robustness could streamline the identification of therapeutic targets. Here, we develop a computational approach to identify robust genetic interactions that can be reproduced across independent experiments and across non-overlapping cell line panels. We used this approach to evaluate >140,000 potential genetic interactions involving cancer driver genes and identified 1,520 that are significant in at least one study but only 220 that reproduce across multiple studies. Analysis of these interactions demonstrated that: (i) oncogene addiction effects are more robust than oncogene-related synthetic lethal effects; and (ii) robust genetic interactions in cancer are enriched for gene pairs whose protein products physically interact. This suggests that protein-protein interactions can be used not only to understand the mechanistic basis of genetic interaction effects, but also to prioritise robust targets for further development. To explore the utility of this approach, we used a protein-protein interaction network to guide the search for robust synthetic lethal interactions associated with passenger gene alterations and validated two novel robust synthetic lethalities.

cancer biology↗

bioRxiv2017

Genome-wide and high-density CRISPR-Cas9 screens identify point mutations in PARP1 causing PARP inhibitor resistance

PARP inhibitors (PARPi) target homologous recombination defective tumour cells via synthetic lethality. Genome-wide and high-density CRISPR-Cas9 \"tag, mutate and enrich\" mutagenesis screens identified single amino acid mutations in PARP1 that cause profound PARPi-resistance. These included PARP1 mutations outside of the DNA interacting regions of the protein, such as mutations in solvent exposed regions of the catalytic domain and clusters of mutations around points of contact between ZnF, WGR and HD domains. These mutations altered PARP1 trapping, as did a mutation found in a clinical case of PARPi resistance. These genetic studies reinforce the importance of trapped PARP1 as a key cytotoxic DNA lesion and suggest that interactions between non-DNA binding domains of PARP1 influence cytotoxicity. Finally, different mechanisms of PARPi resistance (BRCA1 reversion, PARP1, 53BP1, REV7 mutation) had differing effects on chemotherapy sensitivity, suggesting that the underlying mechanism of PARPi resistance likely influences the success of subsequent therapies.

cancer biology↗

bioRxiv2017

A compendium of co-regulated protein complexes in breast cancer reveals collateral loss events

Protein complexes are responsible for the bulk of activities within the cell, but how their behavior and composition varies across tumors remains poorly understood. By combining proteomic profiles of breast tumors with a large-scale protein-protein interaction network, we have identified a set of 258 high-confidence protein complexes whose subunits have highly correlated protein abundance across tumor samples. We used this set to identify complexes that are reproducibly under- or over-expressed in specific breast cancer subtypes. We found that mutation or deletion of one subunit of a complex was often associated with a collateral reduction in protein expression of additional complex members. This collateral loss phenomenon was evident from proteomic, but not transcriptomic, profiles suggesting post-transcriptional control. Mutation of the tumor suppressor E-cadherin (CDH1) was associated with a collateral loss of members of the adherens junction complex, an effect we validated using an engineered model of E-cadherin loss.

cancer biology↗

bioRxiv2016

CancerGD: a resource for identifying and interpreting genetic dependencies in cancer

Genes whose function is selectively essential in the presence of cancer associated genetic aberrations represent promising targets for the development of precision therapeutics. Here we present CancerGD (www.cancergd.org), a resource that integrates genotypic profiling with large-scale loss-of-function genetic screens in tumor cell lines to identify such genetic dependencies. CancerGD provides tools for searching, visualizing, and interpreting these genetic dependencies through the integration of functional interaction networks.

cancer biology↗