Brain metastases present a significant complication in lung cancer with an unmet therapeutic need. In this single-centre, retrospective study, we genotyped a clinico-pathologically well-annotated cohort of consecutively resected brain metastases of lung adenocarcinomas and paired primary tumours, diagnosed from 2000 to 2015, using the Ion Torrent Oncomine Comprehensive Cancer Panel v3. Among 444 consecutive brain metastases, 210 (49%) originated from lung cancer. Analysis was successful in 111 samples, including 54 pairs of brain metastasis and primary tumour. Most driver alterations were preserved in brain metastases. Private alterations exclusive to primary tumours, brain metastases or both sites (intersecting cases) were present in 22%, 26% and 26% of cases, respectively. Seven percent had no shared mutations. KRAS mutations were more frequent in primary tumours metastasised to the brain (32/55, 58%) compared to TCGA (33%, p < 0.005) and own data from routine diagnostics, independent from clinical or pathological characteristics. Fourteen cases showed alterations in the EGFR signalling pathway including additional KRAS alterations that were private to brain metastases. KRAS G12C was detected most frequently (26% of patients) and KRAS G12C and G13C variants were significantly enriched in brain metastases. Synchronous and metachronous cases had a similar mutation profile. Our results suggest an important role of KRAS alterations in the pathobiology of brain metastases from lung adenocarcinomas. This has direct therapeutic implications as inhibitors selectively targeting KRAS G12C are entering the clinics.

Background: The COVID-19 global health crisis has led to an exponential surge in published scientific literature. In an attempt to tackle the pandemic, extremely large COVID-19–related corpora are being created, sometimes with inaccurate information, which is no longer at scale of human analyses. Objective: In the context of searching for scientific evidence in the deluge of COVID-19–related literature, we present an information retrieval methodology for effective identification of relevant sources to answer biomedical queries posed using natural language. Methods: Our multistage retrieval methodology combines probabilistic weighting models and reranking algorithms based on deep neural architectures to boost the ranking of relevant documents. Similarity of COVID-19 queries is compared to documents, and a series of postprocessing methods is applied to the initial ranking list to improve the match between the query and the biomedical information source and boost the position of relevant documents. Results: The methodology was evaluated in the context of the TREC-COVID challenge, achieving competitive results with the top-ranking teams participating in the competition. Particularly, the combination of bag-of-words and deep neural language models significantly outperformed an Okapi Best Match 25–based baseline, retrieving on average, 83% of relevant documents in the top 20. Conclusions: These results indicate that multistage retrieval supported by deep learning could enhance identification of literature for COVID-19–related questions posed using natural language.

Serine/Threonine protein phosphatase 2A (PP2A) is a heterotrimeric (or occasionally, heterodimeric) phosphatase with pleiotropic functions and ubiquitous expression. Despite the fact that they all contribute to protein dephosphorylation, multiple PP2A complexes exist which differ considerably by their subcellular localization and their substrate specificity, suggesting diverse PP2A functions. PP2A complex formation is tightly regulated by means of gene expression regulation by transcription factors, microRNAs, and post-translational modifications. Furthermore, a constant competition between PP2A regulatory subunits is taking place dynamically and depending on the spatiotemporal circumstance; many of the integral subunits can outcompete the rest, subjecting them to proteolysis. PP2A modulation is especially important in the context of brain tumors due to its ability to modulate distinct glioma-promoting signal transduction pathways, such as PI3K/Akt, Wnt, Ras, NF-κb, etc. Furthermore, PP2A is also implicated in DNA repair and survival pathways that are activated upon treatment of glioma cells with chemo-radiation. Depending on the cancer cell type, preclinical studies have shown some promise in utilising PP2A activator or PP2A inhibitors to overcome therapy resistance. This review has a special focus on “glioblastoma, IDH wild-type” (GBM) tumors, for which the therapy options have limited efficacy, and tumor relapse is inevitable.

Adult-type diffuse gliomas, CNS WHO grade 4 are the most aggressive primary brain tumors and represent a particular challenge for therapeutic intervention. In a single-center retrospective study of matched pairs of initial and post-therapeutic glioma cases with a recurrence period greater than 1 year, we performed whole exome sequencing combined with mRNA and microRNA expression profiling to identify processes that are altered in recurrent gliomas. Mutational analysis of recurrent gliomas revealed early branching evolution in 75% of the patients. High plasticity was confirmed at the mRNA and miRNA levels. SBS1 signature was reduced and SBS11 was elevated, demonstrating the effect of alkylating agent therapy on the mutational landscape. There was no evidence for secondary genomic alterations driving therapy resistance. ALK7/ACVR1C and LTBP1 were upregulated, whereas LEFTY2 was downregulated, pointing towards enhanced Tumor Growth Factor β (TGF-β) signaling in recurrent gliomas. Consistently, altered microRNA expression profiles pointed towards enhanced Nuclear Factor Kappa B and Wnt signaling that, cooperatively with TGF-β, induces epithelial to mesenchymal transition (EMT), migration, and stemness. TGF-β-induced expression of pro-apoptotic proteins and repression of antiapoptotic proteins were uncoupled in the recurrent tumor. Our results suggest an important role of TGF-β signaling in recurrent gliomas. This may have clinical implications since TGF-β inhibitors have entered clinical phase studies and may potentially be used in combination therapy to interfere with chemoradiation resistance. Recurrent gliomas show high incidence of early branching evolution. High tumor plasticity is confirmed at the level of microRNA and mRNA expression profiles.

Background: Glioblastoma is the most aggressive primary brain tumor. Although temozolomide induces DNA damage, its efficacy is limited by intrinsic resistance mechanisms, leading to tumor relapse. In this study we aimed to identify microRNA-mediated resistance mechanisms. Methods: MicroRNA screens were performed to identify temozolomide resistance mechanisms. Temozolomide response was evaluated using clonogenic and spheroid assays in glioblastoma cell lines and patient-derived primary cells. DNA damage response was assessed by γH2AX foci formation. Cell cycle distribution, senescence and ferroptosis were assessed following miR-19b attenuation. An orthotopic xenograft and a syngeneic mouse model were used to confirm findings. Results: Our screen and subsequent phosphoprotein analysis identified miR-19b and its target PPP2R5E, a subunit of the phosphatase PP2A, as modulators of temozolomide response. Attenuation of miR-19b upregulated PPP2R5E, inducing genotoxic stress, thereby enhancing temozolomide response. Mechanistically, DNA damage correlated with elevated nuclear ROS, promoting senescence and ferroptosis. Consistently, pharmacological activation of PP2A with FTY720 phenocopied the effects of miR-19b suppression. Conversely, knockdown of PPP2R5E reversed temozolomide sensitisation in vitro, in vivo, and ex vivo models, confirming the critical role of the miR-19b /PPP2R5E axis in modulating drug response. Conclusions: Therapeutic targeting of the PPP2R5E/PP2A complexes holds promise for enhanced temozolomide efficacy in glioblastoma.

Despite the standard of care, glioblastoma IDH wildtype (GBM) inevitably recurs, underscoring the need to develop new treatment strategies. To address the role of microRNAs in temozolomide (TMZ) response, we performed functional microRNA screens and consistently identified miR-19b . Our study reveals a novel axis between miR-19b and PPP2R5E subunit of serine/threonine protein phosphatase PP2A and establishes a so far unappreciated contribution of miR-19b in TMZ resistance of GBM. Specifically, our results demonstrate that attenuation of miR-19b in GBM cell lines and glioblastoma stem cells (GSCs) induces DNA damage, which further enhances the cytotoxic effects of TMZ treatment. We confirmed TMZ resistance induced by knocking down PPP2R5E in orthotopic mouse xenografts of GSCs. Furthermore, our results indicate that treating cells with the PP2A-activating drug FTY720 or knocking down endogenous PP2A-inhibiting proteins potentiates the cytotoxic effects of TMZ. MiR-19b attenuation or PPP2R5E activation could potentially be exploited in adjuvant therapy of GBM patients.