Oncogenic KRAS is a major driver in lung adenocarcinoma (LUAD) that has yet to be therapeutically conquered. Here we report that the SLC7A11/glutathione axis displays metabolic synthetic lethality ...with oncogenic KRAS. Through metabolomics approaches, we found that mutationally activated KRAS strikingly increased intracellular cystine levels and glutathione biosynthesis. SLC7A11, a cystine/glutamate antiporter conferring specificity for cystine uptake, was overexpressed in patients with KRAS-mutant LUAD and showed positive association with tumor progression. Furthermore, SLC7A11 inhibition by either genetic depletion or pharmacological inhibition with sulfasalazine resulted in selective killing across a panel of KRAS-mutant cancer cells in vitro and tumor growth inhibition in vivo, suggesting the functionality and specificity of SLC7A11 as a therapeutic target. Importantly, we further identified a potent SLC7A11 inhibitor, HG106, that markedly decreased cystine uptake and intracellular glutathione biosynthesis. Furthermore, HG106 exhibited selective cytotoxicity toward KRAS-mutant cells by increasing oxidative stress- and ER stress-mediated cell apoptosis. Of note, treatment of KRAS-mutant LUAD with HG106 in several preclinical lung cancer mouse models led to marked tumor suppression and prolonged survival. Overall, our findings reveal that KRAS-mutant LUAD cells are vulnerable to SLC7A11 inhibition, offering potential therapeutic approaches for this currently incurable disease.
No effective targeted therapies exist for cancers with somatic KRAS mutations. Here we develop a synthetic lethal chemical screen in isogenic KRAS-mutant and wild-type cells to identify clinical drug ...pairs. Our results show that dual inhibition of polo-like kinase 1 and RhoA/Rho kinase (ROCK) leads to the synergistic effects in KRAS-mutant cancers. Microarray analysis reveals that this combinatory inhibition significantly increases transcription and activity of cyclin-dependent kinase inhibitor p21(WAF1/CIP1), leading to specific G2/M phase blockade in KRAS-mutant cells. Overexpression of p21(WAF1/CIP1), either by cDNA transfection or clinical drugs, preferentially impairs the growth of KRAS-mutant cells, suggesting a druggable synthetic lethal interaction between KRAS and p21(WAF1/CIP1). Co-administration of BI-2536 and fasudil either in the LSL-KRAS(G12D) mouse model or in a patient tumour explant mouse model of KRAS-mutant lung cancer suppresses tumour growth and significantly prolongs mouse survival, suggesting a strong synergy in vivo and a potential avenue for therapeutic treatment of KRAS-mutant cancers.
Mutational activation of KRAS is a common oncogenic event in lung cancer, yet effective therapies are still lacking. Here, we identify B cell lymphoma 6 (BCL6) as a lynchpin in KRAS-driven lung ...cancer. BCL6 expression was increased upon KRAS activation in lung tumor tissue in mice and was positively correlated with the expression of KRAS-GTP, the active form of KRAS, in various human cancer cell lines. Moreover, BCL6 was highly expressed in human KRAS-mutant lung adenocarcinomas and was associated with poor patient survival. Mechanistically, the MAPK/ERK/ELK1 signaling axis downstream of mutant KRAS directly regulated BCL6 expression. BCL6 maintained the global expression of prereplication complex components; therefore, BCL6 inhibition induced stalling of the replication fork, leading to DNA damage and growth arrest in KRAS-mutant lung cancer cells. Importantly, BCL6-specific knockout in lungs significantly reduced the tumor burden and mortality in the LSL-KrasG12D/+ lung cancer mouse model. Likewise, pharmacological inhibition of BCL6 significantly impeded the growth of KRAS-mutant lung cancer cells both in vitro and in vivo. In summary, our findings reveal a crucial role of BCL6 in promoting KRAS-addicted lung cancer and suggest BCL6 as a therapeutic target for the treatment of this intractable disease.
MEK is a canonical effector of mutant KRAS; however, MEK inhibitors fail to yield satisfactory clinical outcomes in KRAS-mutant cancers. Here, we identified mitochondrial oxidative phosphorylation ...(OXPHOS) induction as a profound metabolic alteration to confer KRAS-mutant non-small cell lung cancer (NSCLC) resistance to the clinical MEK inhibitor trametinib. Metabolic flux analysis demonstrated that pyruvate metabolism and fatty acid oxidation were markedly enhanced and coordinately powered the OXPHOS system in resistant cells after trametinib treatment, satisfying their energy demand and protecting them from apoptosis. As molecular events in this process, the pyruvate dehydrogenase complex (PDHc) and carnitine palmitoyl transferase IA (CPTIA), two rate-limiting enzymes that control the metabolic flux of pyruvate and palmitic acid to mitochondrial respiration were activated through phosphorylation and transcriptional regulation. Importantly, the co-administration of trametinib and IACS-010759, a clinical mitochondrial complex I inhibitor that blocks OXPHOS, significantly impeded tumor growth and prolonged mouse survival. Overall, our findings reveal that MEK inhibitor therapy creates a metabolic vulnerability in the mitochondria and further develop an effective combinatorial strategy to circumvent MEK inhibitors resistance in KRAS-driven NSCLC.
Mitochondrial oxidative phosphorylation induction was a major metabolic rewiring event to confer KRAS-mutant NSCLC resistance to MEK inhibitors. Display omitted
The heterogeneously-distributed hyperthermia in nanomaterial-mediated photothermal therapy commonly results in incomplete tumor eradication and serious damage of health tissue. Here, we found ...autophagy was activated in cancer cells underwent photothermal therapy and the inhibition of autophagy significantly enhanced the efficacy of photothermal killing of cancer cells. A formulation of chloroquine-loaded polydopamine nanoparticles was developed for sensitized photothermal cancer therapy, and the in vitro and in vivo study demonstrated that inhibition of autophagy remarkably augmented the efficacy of photothermal therapy, leading to efficient tumor suppression at a mild temperature. The regulation of autophagy provides a new route to increase the efficacy of photothermal cancer therapy.
The droplet-based patterning of graphene is extremely intriguing and essential for the construction of graphene patterns and their applications in electronic devices. Unfortunately, the fabrication ...of complete and significant graphene micro-rings still faces considerable challenges. We demonstrated an effective and novel method to fabricate graphene micro-rings with continuous and dense edges based on multiple droplets overwriting and coffee-ring effect. The appropriate deposition time interval and regime map to acquire micro-rings were determined. By using the suitable time interval, the enhanced micro-rings which have densely-packed edges with 30 μm in width and 4000 nm in height and discrete inner residuals were printed by droplets overwriting. We attributed the stronger ring patterns to the longer particle migration time and multi-times migration. Moreover, enhanced micro-rings with broader and thicker edges could be fabricated as the overwriting layers increase. This work opens novel perspectives for the graphene micro-rings fabrication, which might contribute to the morphology regulation and prospect applications of graphene materials, as well as the guidance on the self-assembly of other functional materials.
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•Stronger graphene micro-rings were printed by multiple droplets overwriting.•The proper time interval and regime map to acquire micro-rings were determined.•Enhanced micro-rings with 30 μm edge width and 4000 nm edge height were obtained.•Stronger rings were caused by longer migration time and multi-times migration.
Uniform graphene films and micro-patterns are the cornerstones of graphene-based printed electronics. However, disk-like reduced graphene oxide (RGO) sheets trend to concentrate at the edge of the ...drop because of the famous coffee-ring effect, resulting in non-uniform patterns. To understand the physics of coffee-ring formation for RGO droplets on hydrophilic substrates, we propose a mechanical model to elucidate the influence and its mechanism of substrate wettability on the solute migration behavior and solute distribution morphology of RGO droplets. Stronger coffee-ring morphology and a slower velocity transition on the PMMA can be observed as compared to that on the glass slides. An explanation based on the mechanical model is provided as the large contact angle on the PMMA leads to a small hindrance force and finally results in more significant coffee-ring morphology. Remarkably, we have revealed one underlying mechanism by which the hydrophilic substrate with better wettability will form more uniform patterns. This study can provide fundamental insights into the relationship between substrate wettability and RGO sheets distribution morphology. It might contribute to morphology regulation of RGO droplets in the DOD printing of graphene films and micro-patterns.
W-Cu composite powder doped with Ce （1.5 wt.%） was prepared by mechanical alloying （MA）,and the W-Cu contact material was fabricated by hot pressing sintering in an electrical vacuum furnace.The ...microstructure,electric conductivity,hardness,and breakdown voltage of the Ce-doped W-Cu alloy were measured and compared with a conventional W-Cu alloy prepared by powder metallurgy.The results show that microstructural refinement and uniformity can improve the breakdown behavior and the electric arc stability of the Ce-doped W-Cu contact material.Also,the Ce-doped W-Cu contact material shows the characteristic of spreading electric arc,which is beneficial to electric arc erosion.
Theranostic nanoparticles that possess multiple diagnostic modalities and allow spatiotemporally controlled therapies can significantly improve therapeutic outcomes and reduce adverse effects. Here, ...an intelligent and biocompatible theranostic formulation is developed based on dendritic platinum–copper alloy nanoparticles (DPCN) for cancer therapy. DPCN have excellent photothermal effect, and can load anticancer drugs such as doxorubicin in their porous structure and release the loaded drugs in response to near infrared light or moderate acidic stimulus. They also inherently have multimodal imaging modalities. Upon the guidance of photoacoustic imaging, DPCN‐mediated photothermal treatment efficiently inhibits tumor growth in vivo. Furthermore, doxorubicin‐loaded DPCN completely suppress the tumor growth even under a low treatment temperature, which avoids hypothermia‐induced damage to normal tissues. Our study develops an excellent theranostic nanoparticle with inherent multimodal imaging and therapeutic modalities for chemophotothermal cancer therapy.
Dendritic platinum–copper alloy nanoparticles (DPCN) are developed as an excellent theranostic agent. DPCN inherently possess multimodal imaging modalities, photothermal effect, and drug loading capability. Upon the guidance of photoacoustic imaging, DPCN‐mediated chemophotothermal treatment efficiently inhibits the tumor growth in vivo.
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•Straight and uniform nitrogen-doped graphene lines were precisely printed.•The line bulging and jetting instabilities were eliminated by facile total drying.•The outline accuracy was ...denoted by normalized standard deviation of line width.•The hole defects in lines were considerably reduced by overwriting multilayers.
Uniform nitrogen-doped graphene lines with favorable outlines are essential components for graphene-based functional devices. However, the line instability in the droplet printing process would deteriorate the straightness and uniformity of printed lines. In this work, straight and uniform nitrogen-doped graphene lines were precisely fabricated by elaborate regulation of drying and overlapping process between neighboring droplets. The bulging instability and jetting instabilities in the printing process were eliminated at a moderate substrate temperature. The wavy edge and outline fluctuations of printed lines were characterized and reduced by decreasing droplet spacing. The uniformity and consistency of printed lines were enhanced by overwriting multilayers. To the best of our knowledge, a systematic and effective way for the printing of uniform nitrogen-doped graphene lines with favorable outlines was revealed for the first time. This study sheds light on the fabrication of straight and uniform nitrogen-doped graphene lines, which might be employed in the droplet printing process of graphene and other functional materials.
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