Overall signature of acquired KRAS gene changes in advanced non-small cell lung cancer patient with EGFR-TKI resistance.

OBJECTIVE: Numerous scattered case studies continue to demonstrate a strong correlation between acquired KRAS mutations and epidermal growth factor receptor-tyrosine kinase inhibitor resistance in non-small cell lung cancer. However, the comprehensive understanding of the KRAS pathway following the failure of epidermal growth factor receptor-tyrosine kinase inhibitor therapy remains limited. METHODS: We conducted a retrospective evaluation of the next generation sequencing data from 323 patients with advanced non-small cell lung cancer and EGFR-activating mutations after experiencing progression with epidermal growth factor receptor-tyrosine kinase inhibitor therapy. Our analysis specifically focused on the acquired changes to the KRAS gene. RESULTS: Among the 323 patients with advanced non-small cell lung cancer and EGFR-activating mutations who experienced resistance to epidermal growth factor receptor-tyrosine kinase inhibitor therapy, 14 individuals (4.3%) developed resistance due to acquired KRAS alterations. Of these 14 patients, 10 cases (71.4%) were due to KRAS missense mutations, 1 case (7.2%) was due to KRAS gene fusion and 3 cases (21.4%) were due to KRAS amplification. Notably, we identified one newly demonstrated KRAS gene fusion (KRAS and LMNTD1), one KRAS G13D and one KRAS K117N. The emergence of acquired KRAS alterations was often accompanied by novel mutations and high tumor mutation burden, with TP53, CNKN2A, PIK3CA, MYC, STK11, CDK4, BRCA2 and ERBB2 being the most frequently observed concurrent mutations. The median progression-free survival and overall survival for the 14 patients were 5.2 and 7.3 months, respectively. Acquired KRAS missense variants were associated with significantly worse progression-free survival compared with other KRAS variant subtypes (P < 0.028). CONCLUSIONS: This study provides significant evidence of the role of acquired KRAS variants in the development of resistance to epidermal growth factor receptor-tyrosine kinase inhibitor therapy. Our results contribute to the growing body of knowledge on the mutational profiles associated with resistance to epidermal growth factor receptor-tyrosine kinase inhibitor treatment. Furthermore, our study highlights the KRAS gene change as a significant mechanism of resistance to epidermal growth factor receptor-tyrosine kinase inhibitor therapy.

Brigatinib, a newly discovered AXL inhibitor, suppresses AXL-mediated acquired resistance to osimertinib in EGFR-mutated non-small cell lung cancer.

In addition to the classical resistance mechanisms, receptor tyrosine-protein kinase AXL is a main mechanism of resistance to third-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) osimertinib in EGFR-mutated non-small cell lung cancer (NSCLC). Developing an effective AXL inhibitor is important to sensitize osimertinib in clinical application. In this study we assessed the efficacy of brigatinib, a second-generation of anaplastic lymphoma kinase (ALK)-TKI, as a novel AXL inhibitor, in overcoming acquired resistance to osimertinib induced by AXL activation. We established an AXL-overexpression NSCLC cell line and conducted high-throughput screening of a small molecule chemical library containing 510 anti-tumor drugs. We found that brigatinib potently inhibited AXL expression, and that brigatinib (0.5 µM) significantly enhanced the anti-tumor efficacy of osimertinib (1 µM) in AXL-mediated osimertinib-resistant NSCLC cell lines in vitro. We demonstrated that brigatinib had a potential ability to bind AXL kinase protein and further inhibit its downstream pathways in NSCLC cell lines. Furthermore, we revealed that brigatinib might decrease AXL expression through increasing K48-linked ubiquitination of AXL and promoting AXL degradation in HCC827OR cells and PC-9OR cells. In AXL-high expression osimertinib-resistant PC-9OR and HCC827OR cells derived xenograft mouse models, administration of osimertinib (10 mg·kg-1·d-1) alone for 3 weeks had no effect, and administration of brigatinib (25 mg·kg-1·d-1) alone caused a minor inhibition on the tumor growth; whereas combination of osimertinib and brigatinib caused marked tumor shrinkages. We concluded that brigatinib may be a promising clinical strategy for enhancing osimertinib efficacy in AXL-mediated osimertinib-resistant NSCLC patients.

AXIN1/MYC Axis Mediated the Osimertinib Resistance in EGFR Mutant Non-Small Cell Lung Cancer Cells.

Osimertinib, a promising and approved third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), is a standard strategy for EGFR-mutant non-small cell lung cancer (NSCLC) patients. However, developed resistance is unavoidable, which reduces its long-term effectiveness. In this study, RNA sequencing was performed to analyze differentially expressed genes (DEGs). The PrognoScan database and Gene Expression Profiling Interactive Analysis (GEPIA) were used to identify the key genes for clinical prognosis and gene correlation respectively. Protein expression was determined by western blot analysis. Cell viability assay and Ki67 staining were used to evaluate the effect of osimertinib on tumor cells. Finally, we screened out two hub genes, myelocytomatosis oncogene (Myc) and axis inhibition protein 1 (Axin1), upregulated in three osimertinib-resistant cell lines through RNA sequencing and bioinformatics analysis. Next, cell experiment confirmed that expression of C-MYC and AXIN1 were elevated in different EGFR mutant NSCLC cell lines with acquired resistance to osimertinib, compared with their corresponding parental cell lines. Furthermore, we demonstrated that AXIN1 upregulated the expression of C-MYC and mediated the acquired resistance of EGFR mutant NSCLC cells to osimertinib in vitro. In conclusion, AXIN1 affected the sensitivity of EGFR mutant NSCLC to osimertinib via regulating C-MYC expression in vitro. Targeting AXIN1/MYC signaling may be a potential new strategy for overcoming acquired resistance to osimertinib.

Electrotaxis of alveolar epithelial cells in direct-current electric fields.

PURPOSE: This study aims to elucidate the electrotaxis response of alveolar epithelial cells (AECs) in direct-current electric fields (EFs), explore the impact of EFs on the cell fate of AECs, and lay the foundation for future exploitation of EFs for the treatment of acute lung injury. METHODS: AECs were extracted from rat lung tissues using magnetic-activated cell sorting. To elucidate the electrotaxis responses of AECs, different voltages of EFs (0, 50, 100, and 200 mV/mm) were applied to two types of AECs, respectively. Cell migrations were recorded and trajectories were pooled to better demonstrate cellular activities through graphs. Cell directionality was calculated as the cosine value of the angle formed by the EF vector and cell migration. To further demonstrate the impact of EFs on the pulmonary tissue, the human bronchial epithelial cells transformed with Ad12-SV40 2B (BEAS-2B cells) were obtained and experimented under the same conditions as AECs. To determine the influence on cell fate, cells underwent electric stimulation were collected to perform Western blot analysis. RESULTS: The successful separation and culturing of AECs were confirmed through immunofluorescence staining. Compared with the control, AECs in EFs demonstrated a significant directionality in a voltage-dependent way. In general, type Ⅰ alveolar epithelial cells migrated faster than type Ⅱ alveolar epithelial cells, and under EFs, these two types of cells exhibited different response threshold. For type Ⅱ alveolar epithelial cells, only EFs at 200 mV/mm resulted a significant difference to the velocity, whereas for, EFs at both 100 mV/mm and 200 mV/mm gave rise to a significant difference. Western blotting suggested that EFs led to an increased expression of a AKT and myeloid leukemia 1 and a decreased expression of Bcl-2-associated X protein and Bcl-2-like protein 11. CONCLUSION: EFs could guide and accelerate the directional migration of AECs and exert antiapoptotic effects, which indicated that EFs are important biophysical signals in the re-epithelialization of alveolar epithelium in lung injury.

Light-assisted anti-wrinkling on azobenzene-containing polyblend films.

Undesired surface wrinkling is a persistent issue far from being resolved. Here, we report a simple light-assisted strategy to prevent surface wrinkling on azobenzene-containing polyblend films, which is based on the unique photo-responsive behaviors of azobenzene moieties. Upon visible light irradiation, the mechanical strain-induced surface wrinkling of the azo-based polyblend film attached on a pre-strained compliant substrate can be effectively suppressed. The influence of light irradiation conditions and polyblend composition on the wrinkling resistance has been systematically investigated. Notably, empirical scaling laws that can quantify the connection of the critical wrinkling conditions with external and internal factors are derived. This spatiotemporal light-assisted strategy combined with the simple universal blending method would provide a general guideline for the anti-wrinkling purpose in diverse functional material systems/devices.

Polarization-Dependent Ultrasensitive Dynamic Wrinkling on Floating Films Induced by Photo-Orientation of Azopolymer.

Ubiquitous surface wrinkling has been well-studied theoretically and experimentally. How to modulate the stress state of a liquid-supported system for the unexploited wrinkling capabilities remains a challenge. Here we report a simple linearly-polarized-light illumination to spatiotemporally trigger ultrasensitive in situ dynamic wrinkling on a floating azo-film. The smart combination of the liquid substrate with photoresponsive azo-moieties leads to the light-induced ultrafast wrinkling evolution, accompanied by unprecedented sequential wrinkling orientation conversion (from polarization-parallel to polarization-perpendicular). The involved different polarization-dependent sequential photo-orientation for azo side chains and azo-grafted main chains of azopolymers is disclosed experimentally for the first time. Meanwhile, programmable dynamic wrinkling with all-optical switchable surface topographies is available, which has wide application potentials in photoresponsive soft photonics.

VPS34 suppression reverses osimertinib resistance via simultaneously inhibiting glycolysis and autophagy.

Autophagy and glycolysis are associated with osimertinib resistance. The energy complement and dynamic balance between these two processes make it difficult to block the process of drug resistance; breaking the complementary relationship between them may effectively overcome drug resistance. However, the exact mechanisms and the key players for regulating autophagy and glycolysis remain unclear. In this study, we demonstrate that autophagy and glycolysis levels in osimertinib-resistant cells were markedly higher than parental cells, and a dynamic balance existed between them. Inhibition of the class III phosphoinositide 3-kinase vacuolar protein sorting 34 (VPS34) with 3-methyladenine or small interfering RNA can not only inhibit abnormally enhanced autophagy but also inhibit glycolysis by inhibiting the location of epidermal growth factor receptor (EGFR) and the expression of hexokinase II. By demonstrating that VPS34 is the key player controlling autophagy and glycolysis simultaneously, our study may provide a new strategy for overcoming osimertinib resistance for treatment of EGFR-mutant non-small cell lung cancer patients.

Light-Associated Surface Wrinkling-Based Metrology for the Photosoftening Characterization in Azobenzene-Polymer Supramolecular Complexes.

As an intriguing characteristic of azobenzene-containing materials (azo-materials), photoinduced changes in mechanical properties (e.g., photosoftening) have stimulated many efforts both theoretically and experimentally. Here a simple yet powerful tool (i.e., a light-associated surface wrinkling-based method) to study the photosoftening effect in azobenzene-polymer (azo-polymer) supramolecular complexes is reported. The photo-induced modulus decrease of supramolecular complex films is deduced by analyzing the change of critical wrinkle wavelength of strain-induced surface wrinkling, in the case of varying experiment parameters. In particular, thanks to the facile modular tunability of the supramolecular system, the photosoftening effect has been systematically investigated as a function of azo-moiety content and the molecular weight of the host polymer. Notably, a photosoftening coefficient that is related to the chemical composition/structure of azo-polymers is introduced, and a simple formula that can quantify the connection of the photosoftening with external irradiation conditions and internal chemical factors of azo-polymers is derived for the first time. The obtained results are of great importance not only to enhance understanding of the photosoftening mechanism, but also to thoroughly apply it in diverse smart fields.

Applied electric fields suppress osimertinib-induced cytotoxicity via inhibiting FOXO3a nuclear translocation through AKT activation.

Osimertinib is a third-generation epidermal growth factor receptor tyrosine kinase inhibitor against T790M-mutant non-small cell lung cancer (NSCLC). Acquired resistance to osimertinib is a growing clinical challenge that is not fully understood. Endogenous electric fields (EFs), components of the tumor microenvironment, are associated with cancer cell migration and proliferation. However, the impact of EFs on drug efficiency has not been studied. In this study, we observed that EFs counteracted the effects of osimertinib. EFs of 100 mV/mm suppressed osimertinib-induced cell death and promoted cell proliferation. Transcriptional analysis revealed that the expression pattern induced by osimertinib was altered by EFs stimulation. KEGG analysis showed that differential expression genes were mostly enriched in PI3K-AKT pathway. Then, we found that osimertinib inhibited AKT phosphorylation, while EFs stimulation resulted in significant activation of AKT, which could override the effects generated by osimertinib. Importantly, pharmacological inhibition of PI3K/AKT by LY294002 diminished EF-induced activation of AKT and restored the cytotoxicity of osimertinib suppressed by EFs, which proved that AKT activation was essential for EFs to attenuate the efficacy of osimertinib. Furthermore, activation of AKT by EFs led to phosphorylation of forkhead box O3a (FOXO3a), and reduction in nuclear translocation of FOXO3a induced by osimertinib, resulting in decreased expression of Bim and attenuated cytotoxicity of osimertinib. Taken together, we demonstrated that EFs suppressed the antitumor activity of osimertinib through AKT/FOXO3a/Bim pathway, and combination of PI3K/AKT inhibitor with osimertinib counteracted the effects of EFs. Our findings provided preliminary data for therapeutic strategies to enhance osimertinib efficacy in NSCLC patients.

Path-Guided Hierarchical Surface Relief Gratings on Azo-Films Induced by Polarized Light Illumination through Surface-Wrinkling Phase Mask.

Surface relief gratings (SRGs) with hierarchical microstructures are highly needed owing to their diverse applications in various fields. Here, we introduce surface-wrinkling templates as novel nonlithographic phase masks to direct the generation of hierarchical well-prescribed SRGs on nonconformally contacted azo-films by a simple single-beam illumination. The light-induced SRGs have controlled microstructures including single/double/triple wavelengths and single/double orientations as well as their organizations. These microstructures can be well tailored by the wavelength of the surface-wrinkling phase masks and the polarization direction of incident light relative to the wrinkling patterns in the phase masks. Interestingly, we find that the larger wavelength is induced prior to the smaller ones, offering another new strategy to tailor the microstructures of SRGs through simple manipulation of the illumination duration. In particular, path-guided SRGs with unprecedented well-organized hierarchical microstructures have been available in the case of controlled moving of the light illumination through the surface-wrinkling phase mask. As demonstrated, the obtained hierarchical SRGs with the capability of multiple optical inscription/erasure have great application potentials in fields such as confidential information (or pattern) records and encryption/decryption.

Photocontrollable Wrinkle Morphology Evolution on Azo-Based Multilayers for Hierarchical Surface Micropatterns Fabrication.

Inspired by nature, comprehensive understanding and ingenious utilization of the self-organized wrinkling behaviors of the sandwiched multilayer bonded on substrates are important for engineering and/or functional laminated devices design. Herein, we report a facile and effective strategy to regulate the wrinkles morphology evolution and the resultant hierarchical surface micropatterns on azobenzene-based laminated multilayers by visible-light irradiation. Revealed by systematic experiments, the photocontrolled dynamic wrinkle evolutions are triggered by the reversible photoisomerization of azobenzene in the top azopolymer film and are strongly dependent on the intermediate photoinert layers (e.g., polystyrene and oxygen plasma-induced SiO x layer) with the wrinkle-reinforcing effect or the stress relaxation acceleration effect. Interestingly, large-area well-defined hierarchical surface wrinkle patterns could be fabricated on the multilayers upon selective exposure. In the unexposed region, the wrinkles evolved into highly oriented patterns, whereas in the exposed region, they were fully erased or evolved into smaller-wavelength wrinkles. This study not only sheds light on the morphological evolution of the wrinkling laminated composites in engineering and nature but also paves a new avenue to conveniently and controllably realize the hierarchical stimulus-responsive surface patterns.

Determinative Surface-Wrinkling Microstructures on Polypyrrole Films by Laser Writing.

We report a simple and efficient laser-writing strategy to fabricate hierarchical nested wrinkling microstructures on conductive polypyrrole (PPy) films, which enables us to develop advanced functional surfaces with diverse applications. The present strategy adopts the photothermal effect of PPy films to mimick the formation of hierarchical nested wrinkles observed in nature and design controlled microscale wrinkling patterns. Here, the PPy film is grown on a poly(dimethylsiloxane) (PDMS) substrate via oxidation polymerization of pyrrole in an acidic solution, accompanied by in situ self-wrinkling with wavelengths of two different scales (i.e., λ1 and λ2). Subsequent laser exposure of the PPy/PDMS bilayer induces a new surface wrinkling with a larger wavelength (i.e., λ3). Owing to the retention of the initial λ1 wrinkles, we obtain hierarchical nested wrinkles with the smaller λ1 wrinkles nested in the larger λ3 ones. Importantly, we realize the large-scale path-determinative fabrication of complex oriented wrinkling microstructures by controlling the relative motion between the bilayer and the laser. Combined with the induced changes in surface color, surface-wrinkling microstructures, and conductivity in the PPy films, the laser-writing strategy can find broad applications, for example, in modulation of surface wetting properties and fabrication of microcircuits, as demonstrated in this work.

Redox-Switchable Surface Wrinkling on Polyaniline Film.

Here the redox-driven switch between the wrinkled and dewrinkled states on poly-aniline (PANI) film is reported. This switch is derived from the reversible transition in different intrinsic redox states of polyaniline (e.g., between emeraldine salt (ES) and leucoemeraldine base (LEB) or between ES and pernigraniline base (PB)) that are involved in the redox reaction, coupled with the corresponding volume expansion/shrinkage. Interestingly, the as-wrinkled ES film becomes deswollen and dewrinkled when reduced to the LEB state or oxidized to the PB state. Conversely, oxidation of the LEB film or reduction of the PB film into the swollen ES film leads to the reoccurrence of surface wrinkling. Furthermore, the reducibility of the dewrinkled LEB film and the oxidizability of the dewrinkled PB film are well utilized respectively to yield various wrinkled PANI-based composite films.

Patterning Surfaces on Azo-Based Multilayer Films via Surface Wrinkling Combined with Visible Light Irradiation.

Here, a simple combined strategy of surface wrinkling with visible light irradiation to fabricate well tunable hierarchical surface patterns on azo-containing multilayer films is reported. The key to tailor surface patterns is to introduce a photosensitive poly(disperse orange 3) intermediate layer into the film/substrate wrinkling system, in which the modulus decrease is induced by the reversible photoisomerization. The existence of a photoinert top layer prevents the photoisomerization-induced stress release in the intermediate layer to some extent. Consequently, the as-formed wrinkling patterns can be modulated over a large area by light irradiation. Interestingly, in the case of selective exposure, the wrinkle wavelength in the exposed region decreases, while the wrinkles in the unexposed region are evolved into highly oriented wrinkles with the orientation perpendicular to the exposed/unexposed boundary. Compared with traditional single layer-based film/substrate systems, the multilayer system consisting of the photosensitive intermediate layer offers unprecedented advantages in the patterning controllability/universality. As demonstrated here, this simple and versatile strategy can be conveniently extended to functional multilayer systems for the creation of prescribed hierarchical surface patterns with optically tailored microstructures.

Tuning and Erasing Surface Wrinkles by Reversible Visible-Light-Induced Photoisomerization.

Periodic wrinkling across different scales has received considerable attention because it not only represents structure failure but also finds wide applications. How to prevent wrinkling or create desired wrinkling patterns is non-trivial because the dynamic evolution of wrinkles is a highly nonlinear problem. Herein, we report a simple yet powerful method to dynamically tune and/or erase wrinkling patterns with visible light. The light-induced photoisomerization of azobenzene units in azopolymer films leads to stress release and consequently to the erasure of the wrinkles. The wrinkles in unexposed regions are also affected and oriented perpendicular to the exposed boundary during the stress reorganization. Theoretical models were developed to understand the dynamics of the reversible photoisomerization-induced wrinkle evolution. This method can be applied for designing functional materials/devices, for example, for the reversible optical writing/erasure of information as demonstrated here.

Controlling and prevention of surface wrinkling via size-dependent critical wrinkling strain.

Surface wrinkling may occur in a film-substrate system when the applied strain exceeds the critical value. However, the practically required strain for the onset of surface wrinkling can be different from the theoretically predicted value. Here we investigate the film size effect-dependent critical strain for the mechanical strain-induced surface wrinkling via a combination of experiments and theoretical analysis. In the poly(dimethylsiloxane)-based system fabricated by the smart combination of mechanical straining and selective O2 plasma (OP) exposure through Cu grids, the film size effect on the critical wrinkling strain is systematically studied by considering OP exposure duration, the mesh number and geometry of Cu grids. Meanwhile, a simple analytical solution revealing the film size effect is well established, which shows good consistency with the experimental results. This study provides an experimental and theoretical basis for finely tuning the critical wrinkling strain in a simple and quantitative manner, which can find a wide range of applications in such fields as microelectronic circuits and optical devices, where controlling and/or prevention of surface wrinkling are of great importance.

Mesoporous manganese nanocarrier target delivery metformin for the co-activation STING pathway to overcome immunotherapy resistance.

Targeting the stimulator of interferon genes (STING) pathway is a promising strategy to overcome primary resistance to immune checkpoint inhibitors in non-small cell lung cancer with the STK11 mutation. We previously found metformin enhances the STING pathway and thus promotes immune response. However, its low concentration in tumors limits its clinical use. Here, we constructed high-mesoporous Mn-based nanocarrier loading metformin nanoparticles (Mn-MSN@Met-M NPs) that actively target tumors and respond to release higher concentration of Mn2+ ions and metformin. The NPs significantly enhanced the T cells to kill lung cancer cells with the STK11 mutant. The mechanism shows that enhanced STING pathway activation promotes STING, TBKI, and IRF3 phosphorylation through Mn2+ ions and metformin release from NPs, thus boosting type I interferon production. In vivo, NPs in combination with a PD-1 inhibitor effectively decreased tumor growth. Collectively, we developed a Mn-MSN@Met-M nanoactivator to intensify immune activation for potential cancer immunotherapy.

Understanding the dynamics of TKI-induced changes in the tumor immune microenvironment for improved therapeutic effect.

BACKGROUND: The dynamic interplay between tyrosine kinase inhibitors (TKIs) and the tumor immune microenvironment (TME) plays a crucial role in the therapeutic trajectory of non-small cell lung cancer (NSCLC). Understanding the functional dynamics and resistance mechanisms of TKIs is essential for advancing the treatment of NSCLC. METHODS: This study assessed the effects of short-term and long-term TKI treatments on the TME in NSCLC, particularly targeting epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) mutations. We analyzed changes in immune cell composition, cytokine profiles, and key proteins involved in immune evasion, such as laminin subunit γ-2 (LAMC2). We also explored the use of aspirin as an adjunct therapy to modulate the TME and counteract TKI resistance. RESULTS: Short-term TKI treatment enhanced T cell-mediated tumor clearance, reduced immunosuppressive M2 macrophage infiltration, and downregulated LAMC2 expression. Conversely, long-term TKI treatment fostered an immunosuppressive TME, contributing to drug resistance and promoting immune escape. Differential responses were observed among various oncogenic mutations, with ALK-targeted therapies eliciting a stronger antitumor immune response compared with EGFR-targeted therapies. Notably, we found that aspirin has potential in overcoming TKI resistance by modulating the TME and enhancing T cell-mediated tumor clearance. CONCLUSIONS: These findings offer new insights into the dynamics of TKI-induced changes in the TME, improving our understanding of NSCLC challenges. The study underscores the critical role of the TME in TKI resistance and suggests that adjunct therapies, like aspirin, may provide new strategies to enhance TKI efficacy and overcome resistance.

Sialyltransferase ST3GAL4 confers osimertinib resistance and offers strategies to overcome resistance in non-small cell lung cancer.

The third-generation EGFR-TKI osimertinib is widely used in EGFR-mutated positive non-small cell lung cancer (NSCLC) patients, but drug resistance is inevitable. The currently known mechanisms only explain resistance in a small proportion of patients. For most patients, the mechanism of osimertinib resistance is still unclear, especially for EGFR-independent resistance. Herein, we thoroughly investigated the novel mechanism of osimertinib resistance and treatment strategies. We identified that ST3GAL4, a sialyltransferase, catalyzes terminal glycan sialylation of receptor protein tyrosine kinases, which induces acquired resistance to osimertinib in vitro and in vivo. In addition, ST3GAL4 is generally overexpressed in osimertinib-resistant patients with unknown resistance mechanisms. ST3GAL4 modifies MET glycosylation on N785 with sialylation, which antagonizes K48-related ubiquitin-dependent MET degradation and subsequently activates MET and its downstream proliferation signaling pathways. Meanwhile, ST3GAL4 knockdown or inhibition by brigatinib resensitizes resistant non-small cell lung cancer cells to osimertinib in vitro and in vivo This study suggests that ST3GAL4 can induce acquired resistance to osimertinib, which may be an important EGFR-independent resistance mechanism Furthermore, targeting ST3GAL4 with brigatinib provides new strategies to overcome osimertinib resistance.

Controlled free edge effects in surface wrinkling via combination of external straining and selective O2 plasma exposure.

Herein the edge effect from the traction-free boundary condition is utilized to direct the spontaneous surface wrinkling. This boundary condition is attained by a simple combination of mechanical straining and selective exposure of polydimethylsiloxane (PDMS) substrate to O2 plasma (OP) through a copper grid. When the strained PDMS sheet is subjected to selective OP treatment, a patterned heterogeneous surface composed of the OP-exposed "hard" oxidized SiOx region (denoted as D1) and the OP-unexposed "soft" region (denoted as D2) is produced. The subsequent full release of the prestrain (ε(pre)) leads to the selective wrinkling in D1, rather than in D2. It is seen that even in D1, no wrinkling occurs in the vicinity of the D1 edge that is perpendicular to the wavevector. Furthermore, the average wrinkle wavelength in D1 (λ(D1)) is smaller than that of the exposed copper grid-free blank area (λ(blank)). This wavelength decrement between λ(D1) and λ(blank), which can be used to roughly estimate the edge-effect extent, increases with the applied mesh number of copper grids and exposure duration, while decreases with the increase of ε(pre). Meanwhile, there exists a decrease in the amplitude of the patterned wrinkles, when compared with that of the blank region. Additionally, hierarchical wrinkling is induced when the strain-free PDMS substrate is selectively exposed to OP, followed by uniaxial stretching and the subsequent blanket exposure. Consequently, oriented wrinkles perpendicular to the stretching direction are generated in D2. With respect to D1, no wrinkling happens or orthogonal wrinkles occur in this region depending on the applied mesh number, exposure duration, and ε(pre). In the above wrinkling process, the combinative edge effects in two perpendicular directions that are involved sequentially have been discussed.