Biology subjects

Lallous, N.

Publications and source records attributed to Lallous, N..

5 recordsLinked to original sources

bioRxiv2025

Deep Modeling of Gain of Function Mutations on Androgen Receptor

The efficiency of Androgen Receptor (AR) pathway inhibitors for prostate cancer (PCa) is on decline due to resistance mechanisms including the occurrence of gain-of-function mutations on human androgen receptor (AR). Hence, understanding and predicting such mutations is crucial for developing effective PCa treatment strategies. Leveraging accumulated data on clinically relevant AR mutants with recent advances in deep modeling techniques, this study aims to unveil and quantify critical AR mutation-drug relationships. By incorporating molecular descriptors for drugs and mutated genes sequences, this work represented these features as single vectors and demonstrates their effectiveness in modeling AR mutant responses to conventional antiandrogens. The developed approach achieves up to 80% accuracy in predicting the gain-of-function behavior of AR mutants and therefore can potentially uncover unknown agonist/antagonist relationships among mutant-drug pairs.

bioinformatics↗

bioRxiv2025

AR-V7 condensates drive androgen-independent transcription in castration resistant prostate cancer

Biomolecular condensates organize cellular environments and regulate key processes such as transcription. We previously showed that full-length androgen receptor (AR-FL), a major oncogenic driver in prostate cancer (PCa), forms nuclear condensates upon androgen stimulation in androgen-sensitive PCa cells. Disrupting these condensates impairs AR-FL transcriptional activity, highlighting their functional importance. However, resistance to androgen deprivation therapy often leads to castration-resistant prostate cancer (CRPC), driven by constitutively active splice variants like AR variant 7 (AR-V7). The mechanisms underlying AR-V7s role in CRPC remain unclear. In this study, we characterized the condensate-forming ability of AR-V7 and compared its phase behavior with AR-FL across a spectrum of PCa models and in vitro conditions. Our findings indicate that cellular context can influence AR-V7s condensate-forming capacity. Unlike AR-FL, AR-V7 spontaneously forms condensates in the absence of androgen stimulation and functions independently of AR-FL in CRPC models. However, AR-V7 requires a higher concentration to form condensates, both in cellular contexts and in vitro. We further reveal that AR-V7 drives transcription via both condensate-dependent and condensate-independent mechanisms. Using an AR-V7 mutant incapable of forming condensates, while retaining nuclear localization and DNA-binding ability, we reveal that the condensate-dependent regime activates part of the oncogenic KRAS pathway in CRPC models. Genes under this condensate-dependent regime were found to harbor significantly higher numbers of AR-binding sites and exhibited boosted expression in response to AR-V7. These findings uncover a previously unrecognized role of AR-V7 condensate formation in driving oncogenic transcriptional programs and shed light on its unique contribution to CRPC progression. HighlightsO_LIAR-V7 condensates form independently of both androgens and AR-FL in CRPC models. C_LIO_LIAR-V7 mediates condensate-dependent and independent transcription C_LIO_LICondensate-dependent transcription enables boosted expression of oncogenic KRAS genes C_LIO_LICondensate-dependent genes exhibit an exponential increase in expression, with a higher number of AR binding sites potentially playing a key role in their reliance on condensate formation. C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=99 SRC="FIGDIR/small/631986v1_ufig1.gif" ALT="Figure 1"> View larger version (19K): org.highwire.dtl.DTLVardef@16b50d1org.highwire.dtl.DTLVardef@86e3b6org.highwire.dtl.DTLVardef@1cfe7f3org.highwire.dtl.DTLVardef@8532a2_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2022

A bi-functional PARP-HDAC inhibitor with activity in Ewing sarcoma

HDAC inhibition has been shown to induce pharmacological BRCAness in cancer cells with proficient DNA repair activity. This provides a rationale for exploring combination treatments with HDAC and PARP inhibition in cancer types that are insensitive to single-agent PARP inhibitors. Here, we report the concept and characterization of a novel bifunctional PARP inhibitor (kt-3283) with dual activity towards PARP1/2 and HDAC enzymes in Ewing sarcoma cells. Compared to the FDA-approved PARP (olaparib) and HDAC (vorinostat) inhibitors, kt-3283 displayed enhanced cytotoxicity in Ewing sarcoma models. The kt-3283-induced cytotoxicity was associated with a strong S and G2/M cell cycle arrest in the nanomolar concentration range and elevated DNA damage as assessed by {gamma}H2AX tracking and comet assays. In three-dimensional spheroid models of Ewing sarcoma, kt-3283 showed efficacy in lower concentrations than olaparib and vorinostat and kt-3283 inhibited colonization of Ewing sarcoma cells in an ex vivo lung metastasis model. In summary, our data demonstrates the preclinical justification for studying the benefit of dual PARP and HDAC inhibition in the treatment of Ewing sarcoma in a clinical trial and provides proof-of-concept for a bi-functional single-molecule therapeutic strategy.

cancer biology↗

bioRxiv2021

Dynamic phase separation of the androgen receptor and its coactivators to regulate gene expression.

Numerous cancers, including prostate cancer (PCa), are addicted to transcription programs driven by superenhancers (SEs). The transcription of genes at SEs is enabled by the formation of phase-separated condensates by transcription factors and co-activators with intrinsically disordered regions. The androgen receptor (AR), main oncogenic driver in PCa, contains large disordered regions and is co-recruited with the co-activator MED1 to SEs to promote oncogenic programs. In this work, we show that dynamic AR-rich, liquid-like foci form in PCa models upon androgen stimulation and correlate with AR transcriptional activity. The co-activator MED1 plays an essential role in the formation of AR foci while AR antagonists hinder their formation. These results suggest that enhanced compartmentalization of AR and co-activators at SEs may play an important role in the activation of oncogenic transcription programs in PCa. A better understanding of the assembly and the regulation of these AR-rich compartments may provide novel therapeutic options.

cancer biology↗

bioRxiv2020

Deep Learning Modelling of Androgen Receptor Responses to Prostate Cancer Therapies

Gain-of-function mutations in human Androgen Receptor (AR) are amongst major causes of drug resistance in prostate cancer (PCa). Identifying mutations that cause resistant phenotype is of critical importance for guiding treatment protocols as well as for designing drugs that do not elicit adverse responses. However, experimental characterization of these mutations is time consuming and costly, and therefore predictive models are needed to anticipate resistant mutations and to guide drug discovery process. In this work, we leverage experimental data collected on 69 clinically observed and/or literature described AR mutants to train a deep neural network (DNN) to predict their responses to currently used and experimental AR anti-androgens. We demonstrate that the use of DNN provides more accurate prediction of the biological outcome (inhibition, activation, no-response) in AR mutant-drug pairs compared to other machine learning approaches and also allows the use of more general 2D descriptors. Finally, the developed approach was used to predict the effect of the latest AR inhibitor darolutamide on all reported AR mutants.

cancer biology↗