p53-dependent crosstalk between DNA replication integrity and redox metabolism mediated through a NRF2-PARP1 axis.

Mechanisms underlying p53-mediated protection of the replicating genome remain elusive, despite the quintessential role of p53 in maintaining genomic stability. Here, we uncover an unexpected function of p53 in curbing replication stress by limiting PARP1 activity and preventing the unscheduled degradation of deprotected stalled forks. We searched for p53-dependent factors and elucidated RRM2B as a prime factor.

Deep learning based CETSA feature prediction cross multiple cell lines with latent space representation.

Mass spectrometry-coupled cellular thermal shift assay (MS-CETSA), a biophysical principle-based technique that measures the thermal stability of proteins at the proteome level inside the cell, has contributed significantly to the understanding of drug mechanisms of action and the dissection of protein interaction dynamics in different cellular states. One of the barriers to the wide applications of MS-CETSA is that MS-CETSA experiments must be performed on the specific cell lines of interest, which is typically time-consuming and costly in terms of labeling reagents and mass spectrometry time. In this study, we aim to predict CETSA features in various cell lines by introducing a computational framework called CycleDNN based on deep neural network technology.

Up-regulation of SLC7A11/xCT creates a vulnerability to selenocystine-induced cytotoxicity.

The SLC7A11/xCT cystine and glutamate antiporter has emerged as an attractive target for cancer therapy due to its selective overexpression in multiple cancers and its role in preventing ferroptosis. Utilizing pharmacological and genetic approaches in hepatocellular carcinoma cell lines, we demonstrate that overexpression of SLC7A11 engenders hypersensitivity towards l-selenocystine, a naturally occurring diselenide that bears close structural similarity to l-cystine. We find that the abundance of SLC7A11 positively correlates with sensitivity to l-selenocystine, but surprisingly, not to Erastin, an inhibitor of SLC7A11 activity.

Multimodal molecular landscape of response to Y90-resin microsphere radioembolization followed by nivolumab for advanced hepatocellular carcinoma.

Background: Combination therapy with radioembolization (yttrium-90)-resin microspheres) followed by nivolumab has shown a promising response rate of 30.6% in a Phase II trial (CA209-678) for advanced hepatocellular carcinoma (HCC); however, the response mechanisms and relevant biomarkers remain unknown.

Methods: By collecting both pretreatment and on-treatment samples, we performed multimodal profiling of tissue and blood samples and investigated molecular changes associated with favorable responses in 33 patients from the trial.

The effect of inhibition of receptor tyrosine kinase AXL on DNA damage response in ovarian cancer.

AXL is a receptor tyrosine kinase that is often overexpressed in cancers. It contributes to pathophysiology in cancer progression and therapeutic resistance, making it an emerging therapeutic target. The first-in-class AXL inhibitor bemcentinib (R428/BGB324) has been granted fast track designation by the U.

Dependency of NELF-E-SLUG-KAT2B epigenetic axis in breast cancer carcinogenesis.

Cancer cells undergo transcriptional reprogramming to drive tumor progression and metastasis. Using cancer cell lines and patient-derived tumor organoids, we demonstrate that loss of the negative elongation factor (NELF) complex inhibits breast cancer development through downregulating epithelial-mesenchymal transition (EMT) and stemness-associated genes. Quantitative multiplexed Rapid Immunoprecipitation Mass spectrometry of Endogenous proteins (qPLEX-RIME) further reveals a significant rewiring of NELF-E-associated chromatin partners as a function of EMT and a co-option of NELF-E with the key EMT transcription factor SLUG.

PBRM1-deficient PBAF complexes target aberrant genomic loci to activate the NF-κB pathway in clear cell renal cell carcinoma.

PBRM1 encodes an accessory subunit of the PBAF SWI/SNF chromatin remodeller, and the inactivation of PBRM1 is a frequent event in kidney cancer. However, the impact of PBRM1 loss on chromatin remodelling is not well examined. Here we show that, in VHL-deficient renal tumours, PBRM1 deficiency results in ectopic PBAF complexes that localize to de novo genomic loci, activating the pro-tumourigenic NF-κB pathway.

Signalling inhibition by ponatinib disrupts productive alternative lengthening of telomeres (ALT).

Alternative lengthening of telomeres (ALT) supports telomere maintenance in 10-15% of cancers, thus representing a compelling target for therapy. By performing anti-cancer compound library screen on isogenic cell lines and using extrachromosomal telomeric C-circles, as a bona fide marker of ALT activity, we identify a receptor tyrosine kinase inhibitor ponatinib that deregulates ALT mechanisms, induces telomeric dysfunction, reduced ALT-associated telomere synthesis, and targets, in vivo, ALT-positive cells. Using RNA-sequencing and quantitative phosphoproteomic analyses, combined with C-circle level assessment, we find an ABL1-JNK-JUN signalling circuit to be inhibited by ponatinib and to have a role in suppressing telomeric C-circles.

Domain-specific p53 mutants activate EGFR by distinct mechanisms exposing tissue-independent therapeutic vulnerabilities.

Mis-sense mutations affecting TP53 promote carcinogenesis both by inactivating tumor suppression, and by conferring pro-carcinogenic activities. We report here that p53 DNA-binding domain (DBD) and transactivation domain (TAD) mis-sense mutants unexpectedly activate pro-carcinogenic epidermal growth factor receptor (EGFR) signaling via distinct, previously unrecognized molecular mechanisms. DBD- and TAD-specific TP53 mutants exhibited different cellular localization and induced distinct gene expression profiles.

Theranostics application of tumor-initiating cell probe TiY in non-small cell lung cancer.

Tumor-initiating cells (TIC) often elude conventional cancer treatment, which results in metastasis and cancer relapse. Recently, studies have begun to focus on the TIC population in tumors to provide better therapeutic options. Previously, we have reported the successful development of a TIC-specific probe TiY with the binding target as vimentin.

Histone variant H3.3 promotes metastasis in alveolar rhabdomyosarcoma.

The relatively quiet mutational landscape of rhabdomyosarcoma (RMS) suggests that epigenetic deregulation could be central to oncogenesis and tumour aggressiveness. Histone variants have long been recognised as important epigenetic regulators of gene expression. However, the role of histone variants in RMS has not been studied hitherto.

A Randomized Phase 2 Trial of Nivolumab Versus Nivolumab-Ipilimumab Combination in EGFR-Mutant NSCLC.

Introduction: Although immune checkpoint inhibitors (ICIs) have dramatically improved outcomes for nononcogene-addicted NSCLC, monotherapy with programmed cell death protein-1 (PD1) inhibition has been associated with low efficacy in the EGFR-mutant setting. Given the potential for synergism with combination checkpoint blockade, we designed a trial to test the activity of combination nivolumab (N)-ipilimumab (NI) in EGFR-mutant NSCLC.

Methods: This is a randomized phase 2 study (NCT03091491) of N versus NI combination in EGFR tyrosine kinase inhibitor (TKI)-resistant NSCLC, with crossover permitted on disease progression.

Integrative multi-omics landscape of fluoxetine action across 27 brain regions reveals global increase in energy metabolism and region-specific chromatin remodelling.

Depression and anxiety are major global health burdens. Although SSRIs targeting the serotonergic system are prescribed over 200 million times annually, they have variable therapeutic efficacy and side effects, and mechanisms of action remain incompletely understood. Here, we comprehensively characterise the molecular landscape of gene regulatory changes associated with fluoxetine, a widely-used SSRI.

Deficiency of the splicing factor RBM10 limits EGFR inhibitor response in EGFR-mutant lung cancer.

Molecularly targeted cancer therapy has improved outcomes for patients with cancer with targetable oncoproteins, such as mutant EGFR in lung cancer. Yet, the long-term survival of these patients remains limited, because treatment responses are typically incomplete. One potential explanation for the lack of complete and durable responses is that oncogene-driven cancers with activating mutations of EGFR often harbor additional co-occurring genetic alterations.

A Runx1-enhancer Element eR1 Identified Lineage Restricted Mammary Luminal Stem Cells.

Mammary gland homeostasis is maintained by adult tissue stem-progenitor cells residing within the luminal and basal epithelia. Dysregulation of mammary stem cells is a key mechanism for cancer development. However, stem cell characterization is challenging because reporter models using cell-specific promoters do not fully recapitulate the mammary stem cell populations.

Robust delivery of RIG-I agonists using extracellular vesicles for anti-cancer immunotherapy.

The RIG-I pathway can be activated by RNA containing 5' triphosphate, leading to type I interferon release and immune activation. Hence, RIG-I agonists have been used to induce immune responses against cancer as potential immunotherapy. However, delivery of 5' triphosphorylated RNA molecules as RIG-I agonists to tumour cells in vivo is challenging due to the susceptibility of these molecules to degradation.