A systematic analysis of the landscape of synthetic lethality-driven precision oncology.

BACKGROUND: Synthetic lethality (SL) denotes a genetic interaction between two genes whose co-inactivation is detrimental to cells. Because more than 25 years have passed since SL was proposed as a promising way to selectively target cancer vulnerabilities, it is timely to comprehensively assess its impact so far and discuss its future. METHODS: We systematically analyzed the literature and clinical trial data from the PubMed and Trialtrove databases to portray the preclinical and clinical landscape of SL oncology. FINDINGS: We identified 235 preclinically validated SL pairs and found 1,207 pertinent clinical trials, and the number keeps increasing over time. About one-third of these SL clinical trials go beyond the typically studied DNA damage response (DDR) pathway, testifying to the recently broadening scope of SL applications in clinical oncology. We find that SL oncology trials have a greater success rate than non-SL-based trials. However, about 75% of the preclinically validated SL interactions have not yet been tested in clinical trials. CONCLUSIONS: Dissecting the recent efforts harnessing SL to identify predictive biomarkers, novel therapeutic targets, and effective combination therapy, our systematic analysis reinforces the hope that SL may serve as a key driver of precision oncology going forward. FUNDING: Funded by the Samsung Research Funding & Incubation Center of Samsung Electronics, the Institute of Information & Communications Technology Planning & Evaluation (IITP) grant funded by the Republic of Korea government (MSIT), the Kwanjeong Educational Foundation, the Intramural Research Program of the National Institutes of Health (NIH), National Cancer Institute (NCI), and Center for Cancer Research (CCR).

Cr-catalysed ethylene dimerization in an ionic liquid-organic solvent biphasic system with perfect 1-butene selectivity.

Cr-catalyzed ionic liquid-organic biphasic ethylene dimerization was realized with 100% 1-butene selectivity. The perfect α-olefin selectivity can be rationalized in terms of the poor solubility of the oligomerized long-chain olefins in ionic liquids, and enables the establishment of a dimerization process without any complicated and energy-intensive catalyst and byproduct separation processes.

Increased interleukin-6/C-reactive protein levels are associated with the upregulation of the adenosine pathway and serve as potential markers of therapeutic resistance to immune checkpoint inhibitor-based therapies in non-small cell lung cancer.

BACKGROUND: Systemic immune activation, hallmarked by C-reactive protein (CRP) and interleukin-6 (IL-6), can modulate antitumor immune responses. In this study, we evaluated the role of IL-6 and CRP in the stratification of patients with non-small cell lung cancer (NSCLC) treated with immune checkpoint inhibitors (ICIs). We also interrogated the underlying immunosuppressive mechanisms driven by the IL-6/CRP axis. METHODS: In cohort A (n=308), we estimated the association of baseline CRP with objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) in patients with NSCLC treated with ICIs alone or with chemo-immunotherapy (Chemo-ICI). Baseline tumor bulk RNA sequencing (RNA-seq) of lung adenocarcinomas (LUADs) treated with pembrolizumab (cohort B, n=59) was used to evaluate differential expression of purine metabolism, as well as correlate IL-6 expression with PFS. CODEFACS approach was applied to deconvolve cohort B to characterize the tumor microenvironment by reconstructing the cell-type-specific transcriptome from bulk expression. Using the LUAD cohort from The Cancer Genome Atlas (TCGA) we explored the correlation between IL-6 expression and adenosine gene signatures. In a third cohort (cohort C, n=18), plasma concentrations of CRP, adenosine 2a receptor (A2aR), and IL-6 were measured using ELISA. RESULTS: In cohort A, 67.2% of patients had a baseline CRP≥10 mg/L (CRP-H). Patients with CRP-H achieved shorter OS (8.6 vs 14.8 months; p=0.006), shorter PFS (3.3 vs 6.6 months; p=0.013), and lower ORR (24.7% vs 46.3%; p=0.015). After adjusting for relevant clinical variables, CRP-H was confirmed as an independent predictor of increased risk of death (HR 1.51, 95% CI: 1.09 to 2.11) and lower probability of achieving disease response (OR 0.34, 95% CI: 0.13 to 0.89). In cohort B, RNA-seq analysis demonstrated higher IL-6 expression on tumor cells of non-responders, along with a shorter PFS (p<0.05) and enrichment of the purinergic pathway. Within the TCGA LUAD cohort, tumor IL-6 expression strongly correlated with the adenosine signature (R=0.65; p<2.2e-16). Plasma analysis in cohort C demonstrated that CRP-H patients had a greater median baseline level of A2aR (6.0 ng/mL vs 1.3 ng/mL; p=0.01). CONCLUSIONS: This study demonstrates CRP as a readily available blood-based prognostic biomarker in ICI-treated NSCLC. Additionally, we elucidate a potential link of the CRP/IL-6 axis with the immunosuppressive adenosine signature pathway that could drive inferior outcomes to ICIs in NSCLC and also offer novel therapeutic avenues.

AXL and Error-Prone DNA Replication Confer Drug Resistance and Offer Strategies to Treat EGFR-Mutant Lung Cancer.

Anticancer therapies have been limited by the emergence of mutations and other adaptations. In bacteria, antibiotics activate the SOS response, which mobilizes error-prone factors that allow for continuous replication at the cost of mutagenesis. We investigated whether the treatment of lung cancer with EGFR inhibitors (EGFRi) similarly engages hypermutators. In cycling drug-tolerant persister (DTP) cells and in EGFRi-treated patients presenting residual disease, we observed upregulation of GAS6, whereas ablation of GAS6's receptor, AXL, eradicated resistance. Reciprocally, AXL overexpression enhanced DTP survival and accelerated the emergence of T790M, an EGFR mutation typical to resistant cells. Mechanistically, AXL induces low-fidelity DNA polymerases and activates their organizer, RAD18, by promoting neddylation. Metabolomics uncovered another hypermutator, AXL-driven activation of MYC, and increased purine synthesis that is unbalanced by pyrimidines. Aligning anti-AXL combination treatments with the transition from DTPs to resistant cells cured patient-derived xenografts. Hence, similar to bacteria, tumors tolerate therapy by engaging pharmacologically targetable endogenous mutators. SIGNIFICANCE: EGFR-mutant lung cancers treated with kinase inhibitors often evolve resistance due to secondary mutations. We report that in similarity to the bacterial SOS response stimulated by antibiotics, endogenous mutators are activated in drug-treated cells, and this heralds tolerance. Blocking the process prevented resistance in xenograft models, which offers new treatment strategies. This article is highlighted in the In This Issue feature, p. 2483.

Synthetic lethality-mediated precision oncology via the tumor transcriptome.

Precision oncology has made significant advances, mainly by targeting actionable mutations in cancer driver genes. Aiming to expand treatment opportunities, recent studies have begun to explore the utility of tumor transcriptome to guide patient treatment. Here, we introduce SELECT (synthetic lethality and rescue-mediated precision oncology via the transcriptome), a precision oncology framework harnessing genetic interactions to predict patient response to cancer therapy from the tumor transcriptome. SELECT is tested on a broad collection of 35 published targeted and immunotherapy clinical trials from 10 different cancer types. It is predictive of patients' response in 80% of these clinical trials and in the recent multi-arm WINTHER trial. The predictive signatures and the code are made publicly available for academic use, laying a basis for future prospective clinical studies.

Core-Multishell-Structured Digital-Gradient Cathode Materials with Enhanced Mechanical and Electrochemical Durability.

Ni-rich cathode materials provide high energy density, but their structural and surface instability limits their cyclability and thermal stability. As one of the approaches to mitigate this problem, cathode materials comprising Ni-rich high-capacity core wrapped in Mn-rich multiple shells are produced successfully. In contrast to the conventional batch-type process for concentration-gradient materials, a digital-gradient cascade coprecipitation process described here achieves the improvements in productivity and quality consistency needed to move toward large-scale manufacturing. The core-multishell cathode materials produced in this manner not only have longer cycle life and improved rate performance compared to homogeneous Ni-rich cathode materials having the same overall composition, but also show remarkably enhanced thermal stability and low impedance growth characteristics. In a novel attempt to determine the correlation between the mechanical properties of the core-multishell cathode particles and their electrochemical cyclabilities, their breaking force and elasticity were successfully measured using a statistical approach, which indicates that a cathode particle with stable surface composition as well as high breaking force has improved capacity retention and durability. These results guide the realization of long life and high thermal stability in Ni-rich cathode materials through heterogeneous particle engineering.

Electrochemical Performance of Nanosized Disordered LiVOPO4.

ε-LiVOPO4 is a promising multielectron cathode material for Li-ion batteries that can accommodate two electrons per vanadium, leading to higher energy densities. However, poor electronic conductivity and low lithium ion diffusivity currently result in low rate capability and poor cycle life. To enhance the electrochemical performance of ε-LiVOPO4, in this work, we optimized its solid-state synthesis route using in situ synchrotron X-ray diffraction and applied a combination of high-energy ball-milling with electronically and ionically conductive coatings aiming to improve bulk and surface Li diffusion. We show that high-energy ball-milling, while reducing the particle size also introduces structural disorder, as evidenced by 7Li and 31P NMR and X-ray absorption spectroscopy. We also show that a combination of electronically and ionically conductive coatings helps to utilize close to theoretical capacity for ε-LiVOPO4 at C/50 (1 C = 153 mA h g-1) and to enhance rate performance and capacity retention. The optimized ε-LiVOPO4/Li3VO4/acetylene black composite yields the high cycling capacity of 250 mA h g-1 at C/5 for over 70 cycles.

Thermal Stability and Reactivity of Cathode Materials for Li-Ion Batteries.

The thermal stability of electrochemically delithiated Li0.1Ni0.8Co0.15Al0.05O2 (NCA), FePO4 (FP), Mn0.8Fe0.2PO4 (MFP), hydrothermally synthesized VOPO4, LiVOPO4, and electrochemically lithiated Li2VOPO4 is investigated by differential scanning calorimetry (DSC) and thermogravimetric analysis, coupled with mass spectrometry (TGA-MS). The thermal stability of the delithiated materials is found to be in the order of NCA < VOPO4 < MFP < FP. Unlike the layered oxides and MFP, VOPO4 does not evolve O2 on heating. Thus, VOPO4 is less likely to cause a thermal run-away phenomenon in batteries at elevated temperature and so is inherently safer. The lithiated materials LiVOPO4, Li2VOPO4, and LiNi0.8Co0.15Al0.05O2 are found to be stable in the presence of electrolyte, but sealed-capsule high-pressure experiments show a phase transformation of VOPO4 → HVOPO4 → H2VOPO4 when VOPO4 reacts with electrolyte (1 M LiPF6 in EC/DMC = 1:1) between 200 and 300 °C. Using first-principles calculations, we confirm that the charged VOPO4 cathode is indeed predicted to be marginally less stable than FP but significantly more stable than NCA in the absence of electrolyte. An analysis of the reaction equilibria between VOPO4 and EC using a multicomponent phase diagram approach yields products and reaction enthalpies that are highly consistent with the experiment results.

Microfluidic preparation of a highly active and stable catalyst by high performance of encapsulation of polyvinylpyrrolidone (PVP)-Pt nanoparticles in microcapsules.

The encapsulation of active metals in microcapsules would be highly advantageous in maintaining or improving the reaction performance of an array of widely used chemical reactions. However, conventional methods suffer from low uniformity, complicated fabrication steps, sintering, leaching, decline of catalytic activity, and/or poor reusability. Here, we report an efficient microfluidic approach to encapsulate Pt nanoparticle stabilized by polyvinylpyrrolidone (PVP) in photocurable double-emulsion droplets with semipermeable thin shells. The encapsulated catalysts are prepared by the in situ photopolymerization of a double emulsion. The rapid and exquisite microfluidics-based fabrication process successfully generates monodisperse microcapsules without loss of the PVP-Pt nanoparticles, which is the first demonstration of the microfluidic encapsulation of active metal with promising catalytic activity. Specifically, compared to quasi-homogeneous catalysis of PVP-Pt nanoparticles for 4-nitrophenol hydrogenation, the encapsulated PVP-Pt nanoparticles demonstrate excellent catalytic activity, a leaching-proof nature, and high reusability under the same reaction conditions. We envision that the approach described here may be an example of elegant catalyst design to efficiently overcome difficult problems in active-metal encapsulation and to dramatically enhance catalytic activity by taking advantage of the unique aspects of microfluidic methods.

Production of biohydrogen by aqueous phase reforming of polyols over platinum catalysts supported on three-dimensionally bimodal mesoporous carbon.

Now in 3D! Three-dimensionally bimodal carbons (3D-BMC) with mesopores of tunable size (controlled through the polymerization of the carbon precursor) are synthesized. After loading with platinum, the catalysts are used in aqueous phase reforming of polyols, and show superior performance in terms of carbon conversion, hydrogen yield, selectivity, and hydrogen production rate compared to platinum catalysts supported on activated carbon or two-dimensional CMK-3.

Direct synthesis of H2O2 catalyzed by Pd nanoparticles encapsulated in the multi-layered polyelectrolyte nanoreactors on a charged sphere.

A highly efficient and industrially viable catalyst design for the direct synthesis of H(2)O(2) from H(2) and O(2) was realized by the encapsulation of Pd nanoparticles in polyelectrolyte multi-layers on a sulfonated resin. The continuous production of 9.9 wt% H(2)O(2) was achieved under intrinsically safe and non-corrosive conditions without any loss of activity.

Microfluidic synthesis of a cell adhesive Janus polyurethane microfiber.

We present a simple synthetic approach for the preparation of cell attachable Janus polyurethane (PU) microfibers in a microfluidic system. The synthesis was performed by using laminar flows of multiple streams with spontaneous formation of carbon dioxide bubbles resulting in an asymmetrically porous PU microfiber. The fabricated asymmetric microfiber (Janus microfiber) provides two distinctive properties: one is a porous region to promote the cellular adhesion and the other is a nonporous region rendering the mechanical strength of the scaffold. The Janus microfibers show dramatic improvement of cell adhesion, proliferation, and viability over a culture period. Cells cultured on the fibers easily bridged gaps between microfibers by joining together to form a cell sheet. The maximum distance between fibers that fibroblasts bridged is approximately 200 microm over 15 days. The Janus microfiber can be used for not only an alternative 2D cell culture plate but also as a novel 3D scaffold for tissue engineering without any need for elegant surface modification for enhancing cell adhesions.

Novel one-pot route to monodisperse thermosensitive hollow microcapsules in a microfluidic system.

We present a simple one-pot synthetic approach for the preparation of monodisperse thermo-sensitive poly(N-isopropylacrylamide) (PNIPAM) microcapsules in a microfluidic system. Based on the mechanism of shear force-driven break-off, aqueous droplets of monomer solution are continuously generated in an immiscible continuous phase containing photoinitiators. Under UV irradiation, activated initiators are diffused into the interface between the continuous phase and the aqueous droplets, which trigger polymerization of NIPAM monomers. The PNIPAM microcapsules produced are hollow microcapsules with a thin shell membrane, high monodispersity, and fast response to environmental temperature. In addition, the size of microcapsules produced can be manipulated by the flow rate of the continuous phase or aqueous phase and different concentrations of surfactant to control interfacial tension between continuous phase and aqueous phase. Furthermore, the versatility of this approach enables the preparation of monodisperse microcapsules having the capability to encapsulate various materials such as proteins and nanoparticles under mild conditions. The in situ microfluidic synthetic method provides a novel approach for the preparation of monodisperse hollow microcapsules via a one-pot route.

Dendrimer-templated Ag-Pd bimetallic nanoparticles.

Ultrafine dendrimer-templated Ag-Pd bimetallic nanoparticles with various metal compositions have been prepared successfully using silver(I)-bis(oxalato)palladate(II) complex. The use of an oxalate complex, in which two metal ions exist in one complex, is found to be effective in preventing unfavorable silver halide formation and thus suitable for the formation of Ag-Pd bimetallic nanoparticles.

Dendritic chiral auxiliaries on silica: a new heterogeneous catalyst for enantioselective addition of diethylzinc to benzaldehyde.

This article reports the first work on the use of silica supported dendritic chiral auxiliaries for the enantioselective addition of diethylzinc to benzaldehyde: the control of dendrimer propagation on the silica surface is of prime importance to obtain enhanced conversion, selectivity, and enantioselectivity.