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Protoporphyrin IX (PpIX)-based photodynamic therapy (PDT) has shown limited efficacy in nonmuscle-invasive bladder cancer (NMIBC). To improve PDT efficacy, we developed singlet oxygen-cleavable prodrugs. These prodrugs, when combined with PpIX-PDT, induce cancer cell death through both PDT and drug release mechanisms. Inhibition of PpIX efflux was reported to be an effective strategy to improve PpIX-PDT in certain cancer cells. Our main goal was to investigate whether adding an efflux inhibitor to the combination of PpIX and prodrugs can improve the PpIX levels in bladder cancer cells and the release of active drugs, thus improving the overall efficacy of the treatment. We treated bladder cancer cell lines with lapatinib and evaluated intracellular PpIX fluorescence, finding significantly increased accumulation. Combining lapatinib with prodrugs led to significantly reduced cell viability compared to prodrugs or PpIX-PDT alone. The effect of lapatinib depended on the expression level of the efflux pump in bladder cancer cells. Interestingly, lapatinib increased paclitaxel (PTX) prodrug uptake by threefold compared to prodrug alone. Adding an efflux inhibitor (e.g., lapatinib) into bladder instillation solutions could be a straightforward and effective strategy for NMIBC treatment, particularly in tumors expressing efflux pumps, with the potential for clinical translation., (© 2024 American Society for Photobiology.)

5-Aminolevulinic acid (ALA) is a prodrug for protoporphyrin IX (PpIX)-mediated photodynamic therapy (PDT) and fluorescence-guided tumor surgery. We previously reported that lapatinib, a repurposed ABCG2 inhibitor, enhanced ALA-induced PpIX fluorescence and PDT by blocking ABCG2-mediated PpIX efflux. In the present study, we evaluated how the variation in ABCG2 activities/protein levels affected tumor cell response to the enhancement of PpIX/PDT by lapatinib and Ko143, an ABCG2 tool inhibitor. ABCG2 activities and protein levels were determined in a panel of human cancer cell lines. Effects of lapatinib and Ko143 on enhancing ALA-PpIX fluorescence and PDT were evaluated and correlated with tumor cell ABCG2 activities. We found that both lapatinib and Ko143 enhanced ALA-PpIX fluorescence and PDT in a dose-dependent manner, although lapatinib exhibited lower efficacy and potency than Ko143 in nearly all cancer cell lines. The EC 50 of ABCG2 inhibitors for enhancing ALA-PpIX and PDT had a positive correlation with tumor cell ABCG2 activities, indicating that tumor cell lines with lower ABCG2 activities were more sensitive to ABCG2 inhibitors for PpIX/PDT enhancement. Our results suggest that, for optimal therapeutic enhancement, the dose of ABCG2 inhibitors needs to be tailored based on the ABCG2 expression/activity in tumors., (© 2024 American Society for Photobiology.)

Glomerulonephritis remains a major cause of morbidity and mortality in systemic lupus erythematosus (SLE). We have reported that expression of HER2/ErbB2, a member of the EGFR family, is increased in kidneys of patients and mice with lupus nephritis. We therefore asked if EGFR-family inhibition could ameliorate murine lupus nephritis. We used lapatinib, an EGFR-ErbB2 dual kinase inhibitor in female lupus-prone NZBxW/F1 mice, in which lupus onset was accelerated by injecting an IFN-α-expressing adenovirus. Mice received lapatinib (75 mg/Kg) or vehicle from the beginning of the acceleration or after the mice developed severe proteinuria (>300 mg/dL). Autoantibodies, kidney disease and markers of fibrosis and wound healing were analyzed. Exposure to IFNα induced ErbB2 expression in the kidney of lupus prone mice. Lapatinib, administered before but not after renal disease onset, lowered autoantibody titers and lessened immune complex deposition in the kidney. However, lapatinib increased proteinuria, kidney fibrosis and mouse mortality. Lapatinib also inhibited an in vitro wound healing assay testing renal cells. Our results suggest that EGFR-ErbB2 dual kinase inhibitor lapatinib decreases autoimmunity but worsens renal disease in IFNα-accelerated lupus, by increasing fibrosis and inhibiting wound healing. Type I Interferons are highlighted as important regulators of HER2/ErbB2 expression in the kidney. Further studies are required to parse the beneficial aspects of EGFR inhibition on autoimmunity from its negative effects on wound healing in lupus nephritis., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

In recent years, the increase in cancer morbidity and mortality has presented scientists with a major challenge in developing new therapeutic agents against cancer cells. This study aims to characterize the anticancer effects of copper oxide nanoparticles (NPs) conjugated with Lapatinib (CuO@Lapatinib) on breast and lung cancer cell lines. The physicochemical properties of the NPs were characterized by fourier-transform infrared (FT-IR) spectroscopy, X-ray diffraction (XRD), scanning and transmission electron microscopy, energy dispersive X-ray spectroscopy (EDS), dynamic light scattering (DLS), and zeta potential analyses. The antiproliferative potential of the NPs in the breast (MDA-MB-231) and lung (A549) cancer cell lines and a normal cell line (MRC5) was investigated by MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide) assay. Flow cytometry and Hoechst staining were used to evaluate cell apoptosis and cell cycle analysis. The reactive oxygen species (ROS) levels in the treated and control cells were also determined. The NPs were spherical, with a size range of 20-59nm, a DLS size of 338nm, and a zeta potential of -42.9 mV. The half maximal inhibitory concentration (IC 50 ) of CuO@Lapatinib NPs for the normal, breast cancer, and lung cancer cell lines was 105, 98, and 87 µg/ml, respectively. Treatment with CuO@Lapatinib NPs caused considerable apoptosis induction in breast cancer (from 0.65% to 68.96%) and lung cancer cell lines (from 1.11% to 44.11%). Also, an increased level of cell cycle arrest at the S phase was observed in both cancer cell lines. The ROS level in the breast and lung cancer cell lines after treatment with CuO@Lapatinib NPs increased by 3.45 and 21.04 folds, respectively. Nuclear morphological alterations, including chromatin condensation and fragmentation, were observed in both cancer cell lines. This study indicates CuO@Lapatinib is a potent antiproliferative compound with more efficient inhibitory effects on lung cancer than breast cancer cells, which can be related to the higher ROS generation in the A549 cell line., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Although anti-HER2 therapy has made significant strides in reducing metastasis and relapse in HER2-positive breast cancer, resistance to agents like trastuzumab, pertuzumab, and lapatinib frequently develops in patients undergoing treatment. Previous studies suggest that the hyperactivation of the PI3K-AKT signaling pathway by PIK3CA/PTEN gene mutations is implicated in HER2 resistance. In this study, we introduce a novel PI3K-p110α Proteolysis TAargeting Chimera (PROTAC) that effectively inhibits the proliferation of breast cancer cells by degrading PI3K-p110α. When tested in two lapatinib-resistant cell lines, JIMT1 and MDA-MB-453, both of which harbor PIK3CA mutations, the PI3K PROTAC notably reduced cell proliferation and induced G1 phase cell cycle arrest. Importantly, even at very low concentrations, PI3K PROTAC restored sensitivity to lapatinib. Furthermore, the efficacy of PI3K PROTAC surpassed that of Alpelisib, a selective PI3K-p110α kinase inhibitor in clinic. The superior performance of PI3K PROTAC was also confirmed in lapatinib-resistant breast cancer xenograft tumors and patient-derived breast cancer organoids (PDOs). In conclusion, this study reveals that the novel PI3K PROTAC we synthesized could serve as an effective agent to overcome lapatinib resistance., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer and it lacks specific therapeutic targets and effective treatment protocols. By analyzing a proteomic TNBC dataset, we found significant upregulation of sideroflexin 1 (SFXN1) in tumor tissues. However, the precise function of SFXN1 in TNBC remains unclear. Immunoblotting was performed to determine SFXN1 expression levels. Label-free quantitative proteomics and liquid chromatography-tandem mass spectrometry were used to identify the downstream targets of SFXN1. Mechanistic studies of SFXN1 and cellular inhibitor of PP2A (CIP2A) were performed using immunoblotting, immunofluorescence staining, and reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Functional experiments were used to investigate the role of SFXN1 in TNBC cells. SFXN1 was significantly overexpressed in TNBC tumor tissues and was associated with unfavorable outcomes in patients with TNBC. Functional experiments demonstrated that SFXN1 promoted TNBC growth and metastasis in vitro and in vivo. Mechanistic studies revealed that SFXN1 promoted TNBC progression by inhibiting the autophagy receptor TOLLIP (toll interacting protein)-mediated autophagic degradation of CIP2A. The pro-tumorigenic effect of SFXN1 overexpression was partially prevented by lapatinib-mediated inhibition of the CIP2A/PP2A/p-AKT pathway. These findings may provide a new targeted therapy for patients with TNBC., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The role of extracellular matrix (ECM) prevalent in the brain metastatic breast cancer (BMBC) niche in mediating cancer cell growth, survival, and response to therapeutic agents is not well understood. Emerging evidence suggests a vital role of ECM of the primary breast tumor microenvironment (TME) in tumor progression and survival. Possibly, the BMBC cells are also similarly influenced by the ECM of the metastatic niche; therefore, understanding the effect of the metastatic ECM on BMBC cells is imperative. Herein, we assessed the impact of various ECM components (i.e., Tenascin C, Laminin I, Collagen I, Collagen IV, and Fibronectin) on brain metastatic human epidermal growth factor receptor 2 (HER2)-positive and triple negative breast cancer (TNBC) cell lines in vitro. The highly aggressive TNBC cell line was minimally affected by ECM components exhibiting no remarkable changes in viability and morphology. On the contrary, amongst various ECM components tested, the HER2-positive cell line was significantly affected by Laminin I with higher viability and demonstrated a distinct spread morphology. In addition, HER2-positive BMBC cells exhibited resistance to Lapatinib in presence of Laminin I. Mechanistically, Laminin I-induced resistance to Lapatinib was mediated in part by phosphorylation of Erk 1/2 and elevated levels of Vimentin. Laminin I also significantly enhanced the migratory potential and replicative viability of HER2-positive BMBC cells. In sum, our findings show that presence of Laminin I in the TME of BMBC cells imparts resistance to targeted therapeutic agent Lapatinib, while increasing the possibility of its dispersal and clonogenic survival., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Human epidermal growth factor receptor 2 positive (HER2+) breast cancer (BC) tends to metastasize and has a bad prognosis due to its high malignancy and rapid progression. Inositol polyphosphate 4-phosphatase isoenzymes type II (INPP4B) plays unequal roles in the development of various cancers. However, the function of INPP4B in HER2+ BC has not been elucidated. Here we found that INPP4B expression was significantly lower in HER2+ BC and positively correlated with the prognosis by bioinformatics and tissue immunofluorescence analyses. Overexpression of INPP4B inhibited cell proliferation, migration, and growth of xenografts in HER2+ BC cells. Conversely, depletion of INPP4B reversed these effects and activated the PDK1/AKT and Wnt/β-catenin signaling pathways to promote epithelial-mesenchymal transition (EMT) progression. Moreover, INPP4B overexpression blocked epidermal growth factor (EGF) -induced cell proliferation, migration and EMT progression, whereas INPP4B depletion antagonized HER2 depletion in reduction of cell proliferation and migration of HER2+ BC cells. Additionally, Lapatinib (LAP) inhibited HER2+ BC cell survival, proliferation and migration, and its effect was further enhanced by overexpression of INPP4B. In summary, our results illustrate that INPP4B suppresses HER2+ BC growth, migration and EMT, and its expression level affects patient outcome, further providing new insights into clinical practice., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Local recurrence post-surgery in early-stage triple-negative breast cancer is a major challenge. To control the regrowth of a residual tumor, we have developed an autologous therapeutic hybrid fibrin glue for intra-operative implantation. Using autologous serum proteins as stabilizers, we have optimized high drug-loaded lapatinib-NanoSera (Lap-NS; ∼66% L.C.) and imiquimod-MicroSera (IMQ-MS; ∼92% L.C). Additionally, plasmonic nanosera (PNS) with an ∼67% photothermal conversion efficiency under 980 nm laser irradiation was also developed. While localized monotherapy with either Lap-NS or PNS reduced the tumor regrowth rate, their combination with IMQ-MS amplified the effect of immunogenic cell death with a high level of tumor infiltration by immune cells at the surgical site. The localized combination immunotherapy with a Nano-MicroSera based hybrid fibrin implant showed superior tumor inhibition and survival with significant promise for clinical translation.

Breast cancer is the most common malignancy accounting for 12.5% of all newly diagnosed cancer cases across the globe. Breast cancer cells are known to metastasize to distant organs ( i.e. , brain), wherein they can exhibit a dormant phenotype for extended time periods. These dormant cancer cells exhibit reduced proliferation and therapeutic resistance. However, the mechanisms by which dormant cancer cells exhibit resistance to therapy, in the context of brain metastatic breast cancer (BMBC), is not well understood. Herein, we utilized hyaluronic acid (HA) hydrogels with varying stiffnesses to study drug responsiveness in dormant vs. proliferative BMBC cells. It was found that cells cultured on soft HA hydrogels (∼0.4 kPa) that showed a non-proliferative (dormant) phenotype exhibited resistance to Paclitaxel or Lapatinib. In contrast, cells cultured on stiff HA hydrogels (∼4.5 kPa) that showed a proliferative phenotype exhibited responsiveness to Paclitaxel or Lapatinib. Moreover, dormancy-associated resistance was found to be due to upregulation of the serum/glucocorticoid regulated kinase 1 (SGK1) gene which was mediated, in part, by the p38 signaling pathway. Accordingly, SGK1 inhibition resulted in a dormant-to-proliferative switch and response to therapy. Overall, our study demonstrates that matrix stiffness influences dormancy-associated therapy response mediated, in part, via the p38/SGK1 axis.

Introduction: HER2, a tyrosine kinase receptor, is amplified in HER2-positive breast cancer, driving cell signaling and growth. Aim: This study aimed to combat multidrug resistance in Dox-insensitive breast adenocarcinoma by creating a nanoformulation therapy with a tyrosine kinase inhibitor. Methodology: Human serum albumin (HSA) was conjugated with α-D-tocopherol succinate to form nanoaggregates loaded with lapatinib (Lapa). Results: The resulting Lapa@HSA(VE) NPs were 117.2 nm in size and demonstrated IC50 values of 10.25 μg/ml on MCF7 (S) and 8.02 μg/ml on MCF7 (R) cell lines. Conclusion: Lapa@HSA(VE) NPs showed no hepatotoxicity, unlike free Lapa, as seen in acute toxicity studies in rats.

Parkinson's disease (PD) is characterized by the progressive loss of dopaminergic neurons in the substantia nigra. The dopamine D3 receptor (D3R) plays a significant role in the pathogenesis and treatment of PD. Activation of receptor tyrosine kinases (RTKs) inhibits signaling mediated by G protein-coupled receptor (GPCR). Epidermal growth factor receptors (EGFRs) and dopamine D3 receptors in the brain are directly associated with PD, both in terms of its development and potential treatment. Therefore, we investigated the impact of modulating the EGFR, a member of the RTKs family, and the dopamine D3R, a member of the GPCR family. In the present study, 100 mg/kg of lapatinib (LAP) was administered to rotenone-intoxicated rats for three weeks. Our findings indicate that LAP effectively alleviated motor impairment, improved histopathological abnormalities, and restored dopaminergic neurons in the substantia nigra. This restoration was achieved through the upregulation of dopamine D3R and increase of tyrosine hydroxylase (TH) expression, as well as boosting dopamine levels. Furthermore, LAP inhibited the activity of p-EGFR, GRK2, and SCR. Additionally, LAP exhibited antioxidant properties by inhibiting the 4-hydroxynonenal (4-HNE) and PLCγ/PKCβII pathway, while enhancing the antioxidant defense mechanism by increasing GSH-GPX4 pathway. The current study offers insights into the potential repositioning of LAP as a disease-modifying drug for PD. This could be achieved by modulating the dopaminergic system and curbing oxidative stress., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The efficacy of chemotherapeutic drugs in tumor treatment is limited by their toxicity and side effects due to their inability to selectively accumulate in tumor tissue. In addition, chemotherapeutic agents are easily pumped out of tumor cells, resulting in their inadequate accumulation. To overcome these challenges, a drug delivery system utilizing the amphiphilic peptide Pep1 was designed. Pep1 can self-assemble into spherical nanoparticles (PL/Pep1) and encapsulate paclitaxel (PTX) and lapatinib (LAP). PL/Pep1 transformed into nanofibers in an acidic environment, resulting in longer drug retention and higher drug concentrations within tumor cells. Ultimately, PL/Pep1 inhibited tumor angiogenesis and enhanced tumor cell apoptosis. The use of shape-changing peptides as drug carriers to enhance cancer cell apoptosis is promising., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Breast cancer stands as the predominant malignancy and primary cause of cancer-related mortality among females globally. Approximately 25% of breast cancers exhibit HER2 overexpression, imparting a more aggressive tumor phenotype and correlating with poor prognoses. Patients with metastatic breast cancer receiving HER2 tyrosine kinase inhibitors (HER2 TKIs), such as Lapatinib, develop acquired resistance within a year, posing a critical challenge in managing this disease. Here, we explore the potential of Artemisia argyi, a Chinese herbal medicine known for its anti-cancer properties, in mitigating HER2 TKI resistance in breast cancer. Analysis of the Cancer Genome Atlas (TCGA) revealed diminished expression of transmembrane serine protease 2 (TMPRSS2), a subfamily of membrane proteolytic enzymes, in breast cancer patients, correlating with unfavorable outcomes. Intriguingly, lapatinib-responsive patients exhibited higher TMPRSS2 expression. Our study unveiled that the compounds from Artemisia argyi, eriodictyol, and umbelliferone could inhibit the growth of lapatinib-resistant HER2-positive breast cancer cells. Mechanistically, they suppressed HER2 kinase activation by enhancing TMPRSS2 activity. Our findings propose TMPRSS2 as a critical determinant in lapatinib sensitivity, and Artemisia argyi emerges as a potential agent to overcome lapatinib via activating TMPRSS2 in HER2-positive breast cancer. This study not only unravels the molecular mechanisms driving cell death in HER2-positive breast cancer cells induced by Artemisia argyi but also lays the groundwork for developing novel inhibitors to enhance therapy outcomes., (© 2024 Wiley Periodicals LLC.)

Based on the concept of "Evolutionary Traps", targeting survival essential genes obtained during tumor drug resistance can effectively eliminate resistant cells. While, it still faces limitations. In this study, lapatinib-resistant cells were used to test the concept of "Evolutionary Traps" and no suitable target stand out because of the identified genes without accessible drug. However, a membrane protein PDPN, which is low or non-expressed in normal tissues, is identified as highly expressed in lapatinib-resistant tumor cells. PDPN CAR-T cells were developed and showed high cytotoxicity against lapatinib-resistant tumor cells in vitro and in vivo, suggesting that CAR-T may be a feasible route for overcoming drug resistance of tumor based on "Evolutionary Trap". To test whether this concept is cell line or drug dependent, we analyzed 21 drug-resistant tumor cell expression profiles reveal that JAG1, GPC3, and L1CAM, which are suitable targets for CAR-T treatment, are significantly upregulated in various drug-resistant tumor cells. Our findings shed light on the feasibility of utilizing CAR-T therapy to treat drug-resistant tumors and broaden the concept of the "Evolutionary Trap"., Competing Interests: Declaration of Competing Interest The authors declare no conflict interests., (Copyright © 2024. Published by Elsevier Ltd.)

Because of its enhanced antitumor efficacy, lapatinib (LAP) is commonly used clinically in combination with the anthracycline drug doxorubicin (DOX) to treat metastatic breast cancer. While it is well recognized that this combination chemotherapy can lead to an increased risk of cardiotoxicity in adult women, its potential cardiotoxicity in the fetus during pregnancy remains understudied. Here, we aimed to examine the combination of LAP chemotherapy and DOX-induced cardiotoxicity in the fetus using a zebrafish embryonic system and investigate the underlying pathologic mechanisms. First, we examined the dose-dependent cardiotoxicity of combined LAP and DOX exposure in zebrafish embryos, which mostly manifested as pericardial edema, bradycardia, cardiac function decline and reduced survival. Second, we revealed that a significant increase in oxidative stress concurrent with activated MAPK signaling, as indicated by increased protein expression of phosphorylated p38 and Jnk, was a notable pathophysiological event after combined LAP and DOX exposure. Third, we showed that inhibiting MAPK signaling by pharmacological treatment with the p38MAPK inhibitor SB203580 or genetic ablation of the map2k6 gene could significantly alleviate combined LAP and DOX exposure-induced cardiotoxicity. Thus, we provided both pharmacologic and genetic evidence to suggest that inhibiting MAPK signaling could exert cardioprotective effects. These findings have implications for understanding the potential cardiotoxicity induced by LAP and DOX combinational chemotherapy in the fetus during pregnancy, which could be leveraged for the development of new therapeutic strategies., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background: Canine prostatic carcinoma (cPC) is a urogenital tumour with a poor prognosis, for which no effective treatment has been established. Recently, it has been shown that human epidermal growth factor receptor type 2 (HER2) is overexpressed in cPC cells; however, the efficacy of HER2-targeted therapy remains unclear., Aim: Investigate the anti-tumour effect of lapatinib on HER2-positive cPC cell lines., Methods: Two cell lines (muPC and bePC) were established from two dogs with cPC and the effects of lapatinib treatment on cell proliferation, apoptosis, and HER2 downstream signalling were investigated. Furthermore, muPC was used to generate tumour-bearing mice, and the anti-tumour effects of lapatinib were examined in vivo ., Results: Lapatinib treatment inhibited the proliferation and phosphorylation of Erk1/2 and Akt, which are downstream signals of HER2. Furthermore, the TUNEL assay showed that lapatinib induced apoptosis in both cell lines. The muPC-engrafted nude mouse model showed that lapatinib significantly inhibited tumour growth and increased the area of necrotic tumour tissue compared to the vehicle-treated groups., Conclusion: Lapatinib exerts anti-tumour effects on cPC cells by inhibiting HER-2 signalling., Competing Interests: The authors declare that there is no conflict of interest.

The aberrant activation of HER2 has a pivotal role in bone metastasis implantation and progression in several tumor types, including prostate cancer (PC). Trastuzumab and other anti-HER2 therapies, such as lapatinib, have been used in human breast cancer HER2 positive. Although HER2 overexpression has been reported in PC, anti-HER2 therapy response has revealed conflicting results. We investigated the potential of lapatinib in inhibiting cell migration and inducing apoptosis in two human (LNCaP and PC3) and two canine PC cell lines (PC1 and PC2). Cell migration and apoptosis were evaluated by Annexin V/PI analysis after lapatinib treatment. The transcriptome analysis of all cell lines before and after treatment with lapatinib was also performed. We found increased apoptosis and migration inhibition in LNCaP cells (androgen-sensitive cell line), while PC1, PC2, and PC3 cells showed no alterations after the treatment. The transcriptome analysis of LNCaP and PC3 cell lines showed 158 dysregulated transcripts in common, while PC1 and PC2 cell lines presented 82. At the doses of lapatinib used, we observed transcriptional modifications in all cell lines. PI3K/AKT/mTOR pathway were enriched in human PC cells, while canine PC cells showed enrichment of tyrosine kinase antitumor response and HER2-related pathways. In canine PC cells, the apoptosis failed after lapatinib treatment, possibly due to the downregulation of MAPK genes. Prostate cancer cells insensitive to androgens may be resistant to lapatinib through PI3K gene dysregulation. The association of lapatinib with PI3K inhibitors may provide a more effective antitumor response and clinical benefits to PC patients., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Fonseca-Alves et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

HER2 is a crucial therapeutic target in breast cancer, and the survival rate of breast cancer patients has increased because of this receptor's inhibition. However, tumors have shown resistance to this therapeutic strategy due to oncogenic mutations that decrease the binding of several HER2-targeted drugs, including lapatinib, and confer resistance to this drug. Neratinib can overcome this drug resistance and effectively inhibit HER2 signaling and tumor growth. In the present study, we examined the efficacy of lapatinib and neratinib using breast cancer cells by Raman microscopy combined with a deep wavelet scattering-based multivariate analysis framework. This approach discriminated between control cells and drug-treated cells with high accuracy, compared to classical principal component analysis. Both lapatinib and neratinib induced changes in the cellular biochemical composition. Furthermore, the Raman results were compared with the results of several in vitro assays. For instance, drug-treated cells exhibited (i) inhibition of ERK and AKT phosphorylation, (ii) inhibition of cellular proliferation, (iii) cell-cycle arrest, and (iv) apoptosis as indicated by western blotting, real-time cell analysis (RTCA), cell-cycle analysis, and apoptosis assays. Thus, the observed Raman spectral changes are attributed to cell-cycle arrest and apoptosis. The results also indicated that neratinib is more potent than lapatinib. Moreover, the uptake and distribution of lapatinib in cells were visualized through its label-free marker bands in the fingerprint region using Raman spectral imaging. These results show the prospects of Raman microscopy in drug evaluation and presumably in drug discovery.

Triple-negative breast cancer (TNBC) is a deadly breast cancer with a poor prognosis. Pyruvate kinase M2 (PKM2), a key rate-limiting enzyme in glycolysis, is abnormally highly expressed in TNBC. Overexpressed PKM2 amplifies glucose uptake, enhances lactate production, and suppresses autophagy, thereby expediting the progression of oncogenic processes. A high mortality rate demands novel chemotherapeutic regimens at once. Herein, we report the rational development of an imidazopyridine-based thiazole derivative 7d as an anticancer agent inhibiting PKM2. Nanomolar range PKM2 inhibitors with favorable drug-like properties emerged through enzyme assays. Experiments on two-dimensional (2D)/three-dimensional (3D) cell cultures, lactate release assay, surface plasmon resonance (SPR), and quantitative real-time polymerase chain reaction (qRT-PCR) validated 7d preclinically. In vivo , 7d outperformed lapatinib in tumor regression. This investigation introduces a lead-based approach characterized by its clear-cut chemistry and robust efficacy in designing an exceptionally potent inhibitor targeting PKM2, with a focus on combating TNBC.

HER2-positive breast cancer is associated with aggressive behavior and reduced survival rates. Calcitriol restores the antiproliferative activity of antiestrogens in estrogen receptor (ER)-negative breast cancer cells by re-expressing ERα. Furthermore, calcitriol and its analog, EB1089, enhance responses to standard anti-cancer drugs. Therefore, we aimed to investigate EB1089 effects when added to the combined treatment of lapatinib and antiestrogens on the proliferation of HER2-positive breast cancer cells. BT-474 (ER-positive/HER2-positive) and SK-BR-3 (ER-negative/HER2-positive) cells were pre-treated with EB1089 to modulate ER expression. Then, cells were treated with EB1089 in the presence of lapatinib with or without the antiestrogens, and proliferation, phosphorylation array assays, and Western blot analysis were performed. The results showed that EB1089 restored the antiproliferative response to antiestrogens in SK-BR-3 cells and improved the inhibitory effects of the combination of lapatinib with antiestrogens in the two cell lines. Moreover, EB1089, alone or combined, modulated ERα protein expression and reduced Akt phosphorylation in HER2-positive cells. EB1089 significantly enhanced the cell growth inhibitory effect of lapatinib combined with antiestrogens in HER2-positive breast cancer cells by modulating ERα expression and Akt phosphorylation suppression. These results highlight the potential of this therapeutic approach as a promising strategy for managing HER2-positive breast cancer.

BTK and PI3K inhibitors are among the drugs approved for the treatment of patients with lymphoid neoplasms. Although active, their ability to lead to long-lasting complete remission is rather limited, especially in the lymphoma setting. This indicates that tumor cells often develop resistance to the drugs. We started from a marginal zone lymphoma cell line, Karpas-1718, kept under prolonged exposure to the PI3Kδ inhibitor idelalisib until acquisition of resistance, or with no drug. Cells underwent transcriptome, miRNA and methylation profiling, whole-exome sequencing, and pharmacologic screening, which led to the identification of the overexpression of ERBB4 and its ligands HBEGF and NRG2 in the resistant cells. Cellular and genetic experiments demonstrated the involvement of this axis in blocking the antitumor activity of various BTK/PI3K inhibitors, currently used in the clinical setting. Addition of recombinant HBEGF induced resistance to BTK/PI3K inhibitors in parental cells and in additional lymphoma models. Combination with the ERBB inhibitor lapatinib was beneficial in resistant cells and in other lymphoma models already expressing the identified resistance factors. An epigenetic reprogramming sustained the expression of the resistance-related factors, and pretreatment with demethylating agents or EZH2 inhibitors overcame the resistance. Resistance factors were also shown to be expressed in clinical specimens. In conclusion, we showed that the overexpression of ERBB4 and its ligands represents a novel mechanism of resistance for lymphoma cells to bypass the antitumor activity of BTK and PI3K inhibitors and that targeted pharmacologic interventions can restore sensitivity to the small molecules., (©2023 American Association for Cancer Research.)

Lapatinib is a targeted therapeutic inhibiting HER2 and EGFR proteins. It is used for the therapy of HER2-positive breast cancer, although not all the patients respond to it. Using human blood serum samples from 14 female donors (separately taken or combined), we found that human blood serum dramatically abolishes the lapatinib-mediated inhibition of growth of the human breast squamous carcinoma SK-BR-3 cell line. This antagonism between lapatinib and human serum was associated with cancelation of the drug induced G1/S cell cycle transition arrest. RNA sequencing revealed 308 differentially expressed genes in the presence of lapatinib. Remarkably, when combined with lapatinib, human blood serum showed the capacity of restoring both the rate of cell growth, and the expression of 96.1% of the genes expression of which were altered by the lapatinib treatment alone. Co-administration of EGF with lapatinib also restores the cell growth and cancels alteration of expression of 95.8% of the genes specific to lapatinib treatment of SK-BR-3 cells. Differential gene expression analysis also showed that in the presence of human serum or EGF, lapatinib was unable to inhibit the Toll-Like Receptor signaling pathway and alter expression of genes linked to the Gene Ontology term of Focal adhesion.

Human epidermal growth factor receptor 2-positive (HER2 + ) breast cancer is correlated with poor prognosis, the current treatment of which is still based on surgery and adjuvant targeted therapy with monoclonal antibody. Problems of drug resistance hinder the use of monoclonal antibodies. Subsequently, tyrosine kinase inhibitors (TKIs) have been noticed, TKIs have the advantages of multi-targets and reduced drug resistance. However, TKIs that target HER family proteins often cause adverse effects such as liver damage and diarrhea. Thus, TKIs with high selectivity are being developed. TH-4000, a prodrug that generated an active form TH-4000Effector (TH-4000E) under hypoxic condition, was evaluated in this research. We found that TH-4000E ([(E)-4-[[4-(3-bromo-4-chloroanilino)pyrido[3,4-d]pyrimidin-6-yl]amino]-4-oxobut-2-enyl]-dimethyl-[(3-methyl-5-nitroimidazol-4-yl)methyl]azanium) (1-1000 nM) had potent and highly selective toxic effects on HER2 + breast cancer cells and inhibited the phosphorylation of HER family kinases at lower doses than that of Lapatinib and Tucatinib. TH-4000E activated Caspase-3 and induced apoptosis through a reactive oxygen species (ROS)-dependent pathway. The prodrug TH-4000 ([(E)-4-[[4-(3-bromo-4-chloroanilino)pyrido[3,4-d]pyrimidin-6-yl]amino]-4-oxobut-2-enyl]-dimethyl-[(3-methyl-5-nitroimidazol-4-yl)methyl]azanium;bromide) (50 mg/kg) effectively suppressed the tumor growth with less liver damage in mouse tumor models. This hypoxia-targeted strategy has possessed advantage in avoiding drug-induced liver damage, TH-4000 could be a promising drug candidate for the treatment of HER2 + breast cancer., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Endocrine therapy plays a critical role in patients with hormone receptor-positive breast cancer. Endocrine-resistant breast cancer cells exhibit more HER2 signaling proteins (pAKT and pERK) and mesenchymal biomarkers than wild-type cell lines. In head and neck squamous cell carcinoma, the combination of lapatinib and palbociclib demonstrated synergistic inhibitory effects on cell proliferation and suppressed ERK1/2 phosphorylation. The combination of lapatinib and palbociclib at half-maximal inhibitory concentrations resulted in an increasing cytotoxic effect on cell proliferation. Furthermore, invasion activity was significantly decreased when combining two drugs at nontoxic concentrations more than either single drug alone did. The combination also remarkably suppressed epithelial-mesenchymal transition transcription factors, such as Snail and pAKT, more than monotherapy. Combining drugs, particularly lapatinib and palbociclib for targeting endocrine-resistant breast cancer cells whose tumors overexpressed HER2 after resistance to hormonal therapy, demonstrated better antiproliferative, anti-invasive effects, and suppression of EMT protein and pAKT than a single drug. These results could be from the interruption of the EMT process via the AKT pathway. Thus, this study provides preliminary data for applying this combination to patients with endocrine-resistant breast cancer in further clinical trials., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The structural basis of the activation and internalization of EGF receptors (EGFR) is still a matter of debate despite the importance of this target in cancer treatment. Whether agonists induce dimer formation or act on preformed dimers remains discussed. Here, we provide direct evidence that EGF-induced EGFR dimer formation as best illustrated by the very large increase in FRET between snap-tagged EGFR subunits induced by agonists. We confirm that Erlotinib-related TK (tyrosine kinase) inhibitors also induce dimer formation despite the inactive state of the binding domain. Surprisingly, TK inhibitors do not inhibit EGF-induced EGFR internalization despite their ability to fully block EGFR signaling. Only Erlotinib-related TK inhibitors promoting asymmetric dimers could slow down this process while the lapatinib-related ones have almost no effect. These results reveal that the conformation of the intracellular TK dimer, rather than the known EGFR signaling, is critical for EGFR internalization. These results also illustrate clear differences in the mode of action of TK inhibitors on the EGFR and open novel possibilities to control EGFR signaling for cancer treatment., (© 2023 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)

Human embryonic stem cells (hESCs) are predisposed to aneuploidy through continual passages. Some reports indicate more sensitivity of aneuploid hESCs cells to anticancer drugs. The present study was designed to investigate the cytotoxicity of three anticancer drugs (including bortezomib, paclitaxel, and lapatinib) and their effect on aneuploidy rate in hESCs. To create a low-level mosaic cell line, normal hESCs (80%) and trisomic hESCs for chromosomes 12 and 17 (20%) were mixed. The effect of the 3 mentioned anticancer drugs on the chromosomal status was assessed by metaphase spread analysis after selection of the nontoxic conditions. Expression of pluripotency genes was analyzed, and an alkaline phosphatase test was performed to assess pluripotency preservation. Our data showed that treatment with bortezomib, paclitaxel, and lapatinib was nontoxic at 0.01, 0.01, and 0.2 μM concentrations, respectively. Alkaline phosphatase and pluripotency gene expression analyses revealed maintenance of pluripotency following treatment with above-noted nontoxic concentrations. Aneuploid cells were dominant in treated and control groups with a minimum abundance of 70%, with no significant differences between groups. Drug treatments had no negative effect on pluripotency. Insensitivity of aneuploid cells in treatment groups could be related to the specific characteristics of each cell line in response to the drug and the proliferative superiority of cells with trisomies 12 and 17., (© 2023 S. Karger AG, Basel.)

Pan-HER TKIs (pyrotinib, lapatinib) are potent HER2 inhibitors, however, their anti-tumor efficacy on esophageal cancer remains to be elucidated. Using two HER2-positive esophageal cancer cell lines, we observed that both pyrotinib and lapatinib could significantly suppress the activation of HER2 and its downstream signaling. However, pyrotinib showed a potent inhibitory effect at 0.1 µM treatment relative to 1 µM of lapatinib. Moreover, treatment with pyrotinibm, but not lapatinib, markedly reduced the protein level of HER2 through enhancing HER2 ubiquitination level and proteasomal degradation. In vitro and in vivo experiments further revealed that pyrotinib effectively suppresses cancer cell invasion and migration, as well as the growth of tumors in nude mice. Overall, our results suggest that pyrotinib is a superior TKI over lapatinib in inhibiting esophageal cancer cell proliferation and tumorigenic potential, and can be chosen as a neo-adjuvant for esophageal cancer treatment.

Background: Trastuzumab constitutes the fundamental component of initial therapy for patients with advanced human epidermal growth factor receptor 2 (HER-2)-positive gastric cancer (GC). However, the efficacy of this treatment is hindered by substantial challenges associated with both primary and acquired drug resistance. While S-phase kinase associated protein 2 (Skp2) overexpression has been implicated in the malignant progression of GC, its role in regulating trastuzumab resistance in this context remains uncertain. Despite the numerous studies investigating Skp2 inhibitors among small molecule compounds and natural products, there has been a lack of successful commercialization of drugs specifically targeting Skp2., Aim: To discover a Skp2 blocker among currently available medications and develop a therapeutic strategy for HER2-positive GC patients who have experienced progression following trastuzumab-based treatment., Methods: Skp2 exogenous overexpression plasmids and small interfering RNA vectors were utilized to investigate the correlation between Skp2 expression and trastuzumab resistance in GC cells. Q-PCR, western blot, and immunohistochemical analyses were conducted to evaluate the regulatory effect of thioridazine on Skp2 expression. A cell counting kit-8 assay, flow cytometry, a amplex red glucose/glucose oxidase assay kit, and a lactate assay kit were utilized to measure the proliferation, apoptosis, and glycolytic activity of GC cells in vitro. A xenograft model established with human GC in nude mice was used to assess thioridazine's effectiveness in vivo ., Results: The expression of Skp2 exhibited a negative correlation with the sensitivity of HER2-positive GC cells to trastuzumab. Thioridazine demonstrated the ability to directly bind to Skp2, resulting in a reduction in Skp2 expression at both the transcriptional and translational levels. Moreover, thioridazine effectively inhibited cell proliferation, exhibited antiapoptotic properties, and decreased the glucose uptake rate and lactate production by suppressing Skp2/protein kinase B/mammalian target of rapamycin/glucose transporter type 1 signaling pathways. The combination of thioridazine with either trastuzumab or lapatinib exhibited a more pronounced anticancer effect in vivo, surpassing the efficacy of either monotherapy., Conclusion: Thioridazine demonstrates promising outcomes in preclinical GC models and offers a novel therapeutic approach for addressing trastuzumab resistance, particularly when used in conjunction with lapatinib. This compound has potential benefits for patients with Skp2-proficient tumors., Competing Interests: Conflict-of-interest statement: The authors declare no conflict of interest., (©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.)

The process of identifying the protein targets and off-targets of a biologically active compound is of great importance in modern drug discovery. Various chemical proteomics approaches have been established for this purpose. To compare the different approaches, and to understand which method would provide the best results, we have chosen the EGFR inhibitor lapatinib as an example molecule. Lapatinib derivatives were designed using linkers with motifs, including amino (amidation), alkyne (click chemistry) and the diazirine group (photo-affinity). These modified lapatinib analogues were validated for their ability to inhibit EGFR activity in vitro and were shown to pull down purified recombinant EGFR protein. In all of the approaches evaluated here, we identified EGFR as the main protein target from the lysate of immortalised cell line expressing EGFR, thus validating its potential use to identify unknown protein targets. Taken together, the results reported here give insight into the cellular activities of lapatinib.

In clinical trials involving patients with HER2 (ERBB2 receptor tyrosine kinase 2) positive gastric cancer, the efficacy of the HER2-targeted drug lapatinib has proven to be disappointingly poor. Under the persistent pressure exerted by targeted drug therapy, a subset of tumor cells exhibit acquired drug resistance through the activation of novel survival signaling cascades, alongside the proliferation of tumor cells that previously harbored mutations conferring resistance to the drug. This study was undertaken with the aim of elucidating in comprehensive detail the intricate mechanisms behind adaptive resistance and identifying novel therapeutic targets that hold promise in the development of effective lapatinib-based therapies for the specific subset of patients afflicted with gastric cancer. We have successfully established a gastric cancer cell line with acquired lapatinib resistance, designated as HGC-27-LR cells. Utilizing comprehensive coding and noncoding transcriptome sequencing analysis, we have identified key factors that regulate lapatinib resistance in HGC-27 cells. We have compellingly validated that among all the lncRNAs identified in HGC-27-LR cells, a novel lncRNA (long noncoding RNA) named NONHSAT160169.1 was found to be most notably upregulated following exposure to lapatinib treatment. The upregulation of NONHSAT160169.1 significantly augmented the migratory, invasive, and stemness capabilities of HGC-27-LR cells. Furthermore, we have delved into the mechanism by which NONHSAT160169.1 regulates lapatinib resistance. The findings have revealed that NONHSAT160169.1, which is induced by the p-STAT3 (signal transducer and activator of transcription 3) nuclear transport pathway, functions as a decoy that competitively interacts with hsa-let-7c-3p and thereby abrogates the inhibitory effect of hsa-let-7c-3p on SOX2 (SRY-box transcription factor 2) expression. Hence, our study has unveiled the NONHSAT160169.1/hsa-let-7c-3p/SOX2 signaling pathway as a novel and pivotal axis for comprehending and surmounting lapatinib resistance in the treatment of HER2-positive gastric cancer., (© 2023. The Author(s).)

To provide complementary information and reveal the molecular characteristics and therapeutic insights of HER2-low breast cancer, we performed this multiomics study of hormone receptor-negative (HR-) and HER2-low breast cancer, also known as HER2-low triple-negative breast cancer (TNBC), and identified 3 subgroups: basal-like, receptor tyrosine kinase-relevant (TKR), and mesenchymal stem-like. These 3 subgroups had distinct features and potential therapeutic targets and were validated in external data sets. Interestingly, the TKR subgroup (which exists in both HR+ and HR- breast cancer) had activated HER2 and downstream MAPK signaling. In vitro and in vivo patient-derived xenograft experiments revealed that pretreatment of the TKR subgroup with a tyrosine kinase inhibitor (lapatinib or tucatinib) could inhibit HER2 signaling and induce accumulated expression of nonfunctional HER2, resulting in increased sensitivity to the sequential HER2-targeting, Ab-drug conjugate DS-8201. Our findings identify clinically relevant subgroups and provide potential therapeutic strategies for HER2-low TNBC subtypes.

A new series of thiazolyl-pyrazoline derivatives ( 4a - d , 5a - d 6a , b , 7a - d , 8a , b , and 10a , b ) have been designed and synthesized through the combination of thiazole and pyrazoline moieties, starting from the key building blocks pyrazoline carbothioamides ( 1a - b ). These eighteen derivatives have been designed as anticipated EGFR/HER2 dual inhibitors. The efficacy of the developed compounds in inhibiting cell proliferation was assessed using the breast cancer MCF-7 cell line. Among the new synthesized thiazolyl-pyrazolines, compounds 6a , 6b , 10a , and 10b displayed potent anticancer activity toward MCF-7 with IC 50 = 4.08, 5.64, 3.37, and 3.54 µM, respectively, when compared with lapatinib (IC 50 = 5.88 µM). In addition, enzymatic assays were also run for the most cytotoxic compounds ( 6a and 6b ) toward EGFR and HER2 to demonstrate their dual inhibitory activity. They revealed promising inhibition potency against EGFR with IC 50 = 0.024, and 0.005 µM, respectively, whereas their IC 50 = 0.047 and 0.022 µM toward HER2, respectively, compared with lapatinib (IC 50 = 0.007 and 0.018 µM). Both compounds 6a and 10a induced apoptosis by arresting the cell cycle of the MCF-7 cell line at the G1 and G1/S phases, respectively. Molecular modeling studies for the promising candidates 6a and 10a showed that they formed the essential binding with the crucial amino acids for EGFR and HER2 inhibition, supporting the in vitro assay results. Furthermore, ADMET study predictions were carried out for the compounds in the study.

Targeting host factors exploited by multiple viruses could offer broad-spectrum solutions for pandemic preparedness. Seventeen candidates targeting diverse functions emerged in a screen of 4,413 compounds for SARS-CoV-2 inhibitors. We demonstrated that lapatinib and other approved inhibitors of the ErbB family of receptor tyrosine kinases suppress replication of SARS-CoV-2, Venezuelan equine encephalitis virus (VEEV), and other emerging viruses with a high barrier to resistance. Lapatinib suppressed SARS-CoV-2 entry and later stages of the viral life cycle and showed synergistic effect with the direct-acting antiviral nirmatrelvir. We discovered that ErbB1, ErbB2, and ErbB4 bind SARS-CoV-2 S1 protein and regulate viral and ACE2 internalization, and they are required for VEEV infection. In human lung organoids, lapatinib protected from SARS-CoV-2-induced activation of ErbB-regulated pathways implicated in non-infectious lung injury, proinflammatory cytokine production, and epithelial barrier injury. Lapatinib suppressed VEEV replication, cytokine production, and disruption of blood-brain barrier integrity in microfluidics-based human neurovascular units, and reduced mortality in a lethal infection murine model. We validated lapatinib-mediated inhibition of ErbB activity as an important mechanism of antiviral action. These findings reveal regulation of viral replication, inflammation, and tissue injury via ErbBs and establish a proof of principle for a repurposed, ErbB-targeted approach to combat emerging viruses.

Pancreatic cancer cells undergo intricate metabolic reprogramming to sustain their survival and proliferation. p53 exhibits a dual role in tumor cell ferroptosis. However, the precise role and mechanisms underlying wild-type p53 activation in promoting ferroptosis in pancreatic cancer cells remain obscure. In this study, we applied bioinformatics tools and performed an analysis of clinical tissue sample databases and observed a significantly upregulated expression of solute carrier family 35 member F2 (SLC35F2) in pancreatic cancer tissues. Our clinical investigations indicated that elevated SLC35F expression was related to adverse survival outcomes. Through multi-omics analyses, we discerned that SLC35F2 influences the transcriptome and inhibits ferroptosis in pancreatic cancer cells. Moreover, our findings reveal the pivotal involvement of p53 in mediating SLC35F2-mediated ferroptosis, both in vitro and in vivo. SLC35F2 inhibits ferroptosis by facilitating TRIM59-mediated p53 degradation. Further mechanistic investigations demonstrated that SLC35F2 competitively interacts with the E3 ubiquitin ligase SYVN1 of TRIM59, thereby stabilizing TRIM59 expression and consequentially promoting p53 degradation. Utilizing protein 3D structure analysis and drug screening, we identified irinotecan hydrochloride and lapatinib ditosylate as compounds targeting SLC35F2, augmenting the antitumor effect of imidazole ketone erastin (IKE) in a wild-type p53 patient-derived xenograft (PDX) model. However, in the p53 mutant PDX model, irinotecan hydrochloride and lapatinib ditosylate did not alter the sensitivity of the tumor xenograft model to IKE-triggered ferroptosis. In summary, our work establishes a novel mechanism wherein the SLC35F2-SYVN1-TRIM59 axis critically regulates ferroptosis of pancreatic cancer cells by inhibiting endogenous p53. Thus, SLC35F2 emerges as a promising therapeutic target for treating pancreatic cancer., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Prolonged treatment of HER2+ breast cancer with lapatinib (LAP) causes cellular senescence and acquired drug resistance, which often associating with poor prognosis for patients. We aim to explore the correlation between cellular senescence and LAP resistance in HER2+ breast cancer, screen for molecular marker of reversible senescence, and construct targeted nanobubbles for ultrasound molecular imaging to dynamically evaluate LAP resistance., Methods and Results: In this study, we established a new cellular model of reversible cellular senescence using LAP and HER2+ breast cancer cells and found that reversible senescence contributed to LAP resistance in HER2+ breast cancer. Then, we identified ecto-5'-nucleotidase (NT5E) as a marker of reversible senescence in HER2+ breast cancer. Based on this, we constructed NT5E-targeted nanobubbles (NT5E-FITC-NBs) as a new molecular imaging modality which could both target reversible senescent cells and be used for ultrasound imaging. NT5E-FITC-NBs showed excellent physical and imaging characteristics. As an ultrasound contrast agent, NT5E-FITC-NBs could accurately identify reversible senescent cells both in vitro and in vivo., Conclusions: Our data demonstrate that cellular senescence-based ultrasound-targeted imaging can identify reversible senescence and evaluate LAP resistance effectively in HER2+ breast cancer cells, which has the potential to improve cancer treatment outcomes by altering therapeutic strategies ahead of aggressive recurrences., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Parkinson's disease (PD) is a neurodegenerative disorder characterized by motor deficits induced by dopaminergic neuronal death in the substantia nigra (SN). Finding a successful neuroprotective therapy is still challenging despite improved knowledge of the etiology of PD and a variety of medications intended to reduce symptoms. Lapatinib (LAP), an FDA-approved anti-cancer medication, has been stated to exert its effect through the modulation of oxidative stress. Furthermore, recent studies display the neuroprotective effects of LAP in epilepsy, encephalomyelitis, and Alzheimer's disease in rodent models through the modulation of oxidative stress and ferroptosis. Nevertheless, it is questionable whether LAP exerts neuroprotective effects in PD. In the current study, administration of 100 mg/kg LAP in rotenone-treated rats for 21 days ameliorates motor impairment, debilitated histopathological alterations, and revived dopaminergic neurons by increasing tyrosine hydroxylase (TH) expression in SN, along with increased dopamine level. LAP remarkably restored the antioxidant defense mechanism system, GPX4/GSH/NRF2 axis, inhibiting oxidative markers, including iron, TfR1, PTGS2, and 4-HNE, along with suppression of p-EGFR/c-SRC/PKCβII/PLC-γ/ACSL-4 pathway. Moreover, LAP modulates HSP90/CDC37 chaperone complex, regulating many key pathological markers of PD, including LRRK2, c-ABL, and α-syn. It is concluded that LAP has neuroprotective effects in PD via modulation of many key parameters implicated in PD pathogenesis. Taken together, the current study offers insights into the potential repositioning of LAP as a disease-modifying drug in PD., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Purpose: HER2-positive breast cancer has a high chance of achieving pathological complete response when HSD17B4, responsible for peroxisomal β-oxidation of very long-chain fatty acids (VLCFA) and estradiol, is methylation-silenced. Here, we aimed to identify the underlying molecular mechanism., Methods: Using a HER2-positive breast cancer cell line, BT-474, control and knock-out (KO) clones were obtained. Metabolic characteristics were analyzed using a Seahorse Flux analyzer., Results: HSD17B4 KO suppressed cellular proliferation, and enhanced sensitivity to lapatinib approximately tenfold. The KO led to accumulation of VLCFA and a decrease of polyunsaturated fatty acids (PUFAs), such as docosahexaenoic acid (DHA) and arachidonic acid. HSD17B4 KO increased Akt phosphorylation, possibly via decreased DHA, and genes involved in oxidative phosphorylation (OxPhos) and electron transport chain (ETC) were upregulated. Increased mitochondrial ATP production in the KO cells was confirmed by extracellular flux analyzer. Increased OxPhos led to severe dependence of the KO cells on pyruvate from glycolysis. Suppression of glycolysis by lapatinib led to severe delayed suppression of OxPhos in KO cells., Conclusion: HSD17B4 KO in BT-474 cells caused a decrease of PUFAs, increased Akt phosphorylation, enhanced glucose dependence of OxPhos, and increased sensitivity to inhibition of HER2, upstream of Akt. This mechanism may be applicable to other HER2-positive glucose-dependent breast cancer cells with HSD17B4 silencing., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Fulvestrant (F), lapatinib (L), and paclitaxel (P) are hydrophobic, anticancer drugs used in the treatment of estrogen receptor (ER) and epidermal growth factor receptor (EGFR)-positive breast cancer. In this study, glycidylated PAMAM G4 dendrimers, substituted with F, L, and/or P and targeting tumor cells, were synthesized and characterized, and their antitumor activity against glioma U-118 MG and non-small cell lung cancer A549 cells was tested comparatively with human non-tumorogenic keratinocytes (HaCaT). All cell lines were ER+ and EGFR+. In addition, the described drugs were tested in the context of antinematode therapy on C. elegans . The results show that the water-soluble conjugates of G4P, G4F, G4L, and G4PFL actively entered the tested cells via endocytosis due to the positive zeta potential (between 13.57-40.29 mV) and the nanoparticle diameter of 99-138 nm. The conjugates of G4P and G4PFL at nanomolar concentrations were the most active, and the least active conjugate was G4F. The tested conjugates inhibited the proliferation of HaCaT and A549 cells; in glioma cells, cytotoxicity was associated mainly with cell damage (mitochondria and membrane transport). The toxicity of the conjugates was proportional to the number of drug residues attached, with the exception of G4L; its action was two- and eight-fold stronger against glioma and keratinocytes, respectively, than the equivalent of lapatinib alone. Unfortunately, non-cancer HaCaT cells were the most sensitive to the tested constructs, which forced a change in the approach to the use of ER and EGFR receptors as a goal in cancer therapy. In vivo studies on C. elegans have shown that all compounds, most notably G4PFL, may be potentially useful in anthelmintic therapy.

In this work, we described a photocatalytic approach, termed ligand-directed photodegradation of interacting proteins (LDPIP), for efficient protein-protein heterodimer degradation. This LDPIP approach utilizes a combination of a photosensitizing protein ligand and appropriate light and molecular oxygen to induce oxidative damage to the ligand-binding protein as well as its interacting protein partner. As a showcase study, a photosensitizing HER2 ligand HER-PS-I was rationally designed based on the FDA-approved HER2 inhibitor lapatinib to efficiently degrade HER2 together with its interacting protein partner HER3, which is thought to induce HER2-targeted therapy resistance and difficult to target by small molecules. HER-PS-I exhibited excellent anticancer activity against drug-resistant MDA-MB-453 cells and its three-dimensional multicellular spheroids. We hope that this LDPIP approach would find more applications in degrading proteins that are thought undruggable or difficult to drug.

Background: We previously established a patient-derived xenograft (PDX) model, patient-derived organoids (PDOs), and PDX-derived organoids (PDXOs) for salivary duct carcinoma (SDC). Using these models, this study examined the therapeutic effect of human epidermal growth factor receptor 2 (HER2) blockade on HER2-positive SDC., Methods: The therapeutic effect of lapatinib was assessed in SDC PDXOs with regards to cell growth, receptor/downstream signaling molecule expression, phosphorylation levels, and apoptosis. Effect of lapatinib treatment was evaluated in vivo in SDC PDX mice., Results: The siRNA knockdown of HER2 and lapatinib suppressed cell proliferation in SDC PDXOs. Lapatinib inhibited the phosphorylation of HER2 and its downstream targets, and induced apoptosis in SDC PDXOs. Lapatinib also significantly reduced tumor volumes compared with that of the control in SDC PDX mice., Conclusion: For the first time, we demonstrated the efficacy of anti-HER2 therapy in HER2-positive SDC using preclinical models of SDC PDX and PDXO., (© 2023 Wiley Periodicals LLC.)

ErbB1 and ErbB2 are the most important biological targets in cancer drug discovery and development of dual inhibitors for the cancer therapy. FDA approved drugs and Neuropep peptides were used to fit into the ATP binding site of the tyrosine kinases; ErbB1 and ErbB2 proteins. Cytoscape, iGEMDOCK, HPEPDOCK and DataWarrior softwares were used to study the role of these agents as anticancer drugs. Eleven FDA approved drugs and eleven Neuropep peptides showed the strongest 2D interactions and significant binding energy with the proteins. Invitro MTT anticancer assay revealed that, the test compounds, peptide YSFGL and doxorubicin showed significant IC 50 value (µM) of 26.417±0.660 and 7.675±0.278 respectively which are compared with the lapatinib standard IC 50 value (µM) of 2.380±0.357 against A549 cells and IC 50 value (µM) of 39.047±0.770 and 8.313±0.435 respectively which are compared with the lapatinib standard IC 50 value (µM) of 3.026±0.180 against MDA-MB-231 cells., Competing Interests: The authors declare that they have no conflict of interests, (Thieme. All rights reserved.)

Newly designed 4 - aminoquinazoline derivatives (5a-f, 6a, b, 7, 8, 9, 10a-c, 11a, b, 12a, b and 13a, b) have been synthesized and evaluated for their potential multitarget anticancer activities, apoptotic and anti-proliferative effects. Thereupon, in vitro cytotoxic activities of all the synthesized compounds were screened against NCI 60 human cancer cell lines (nine subpanels) at NCI, USA. Successfully, 2-morpholino-N-(quinazolin-4-yl) acetohydrazide 5e was granted an NSC code, owing to its significant potency and broad spectrum of activity against various cancer cell lines; leukemia K-562, non-small cell lung cancer NCI-H522 cells, colon cancer SW-620, melanoma LOX IMVI, MALME-3M, renal cancer RXF 393, ACHN and breast cancer MDA-MB231/ATCC (GI% = 99.6, 161, 126.03, 90.22, 174.47, 139.7, 191 and 97, respectively). Compound 5e showed the best inhibitory activity (GI 50  = 1.3 µM) against melanoma LOX IMVI, when tested at five doses against NCI 60 cell lines. Furthermore, compound 5e showed comparable EGFR and CDK2 inhibitory activity results (IC 50  = 0.093 ± 0.006 μM and 0.143 ± 0.008 μM, respectively) to those of lapatinib and ribociclib (IC 50  = 0.03 ± 0.002 μM and 0.067 ± 0.004 μM, respectively). Western blotting analysis of compound 5e against melanoma LOX IMVI marked out significant reduced EGFR and CDK2 protein expression percentages, up to 32.97% and 34.09%, respectively, if compared to lapatinib (31.18%) and ribociclib (29.66%). Moreover, compound 5e caused clear cell cycle arrests at S phase of renal UO-31 cells and at G1 phase of both breast cancer MCF7 and ovarian cancer IGROV1, associated with remarkable increase of DNA content of the controls. In accordance, it demonstrated promising anti- proliferative and apoptotic activities, showing a significant increase in total apoptotic percentages of renal cancer UO-31, breast cancer MCF7 and ovarian IGROV1 cancer cell lines, if compared to the control untreated cells (from 1.79% to 46.72%, 2.19% to 39.02% and 1.66 to 42.51%, respectively). Molecular modelling and dynamic simulation study results supported the main objectives of the present work., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Although nanocarriers have been widely applied in the delivery of anticancer drugs, many commercialized anticancer nanodrug systems still suffer from the problem of being easily trapped by lysosomes, which severely limits the drug delivery efficiency of a nanodrug system. Meanwhile, in drug-resistant tumors, the efflux of anticancer therapeutic drugs via the drug efflux transporters on the plasma membrane of cancer cells can significantly decrease the intracellular drug concentration and lead to the failure of the drug treatment. Here, we developed a small-molecule tyrosine kinase inhibitor (TKI)- and doxorubicin (Dox, a common anticancer drug)-loaded membrane fusion liposome (MFL) (termed Dox@Lapa-MFL) to achieve tumor cell membrane fusion-mediated drug delivery and enhanced chemotherapy of drug-resistant tumor. MFL could deliver drugs in a membrane fusion manner, circumventing the capture by lysosomes. Lapatinib, as the TKI doped in the MFL, could inhibit the efflux of Dox by ATP-binding cassette transporters (ABC transporters), further promoting the intracellular Dox accumulation. As a result, Dox achieved effective killing of drug-resistant tumors under the dual effect of MFL and lapatinib. To the best of our knowledge, it is the first example that employs membrane fusion-mediated TKI delivery for achieving tumor chemosensitization with good biosafety. This work presents an efficient and easily achievable strategy for treating drug-resistant tumors, which may hold promise for clinical applications., Competing Interests: Declaration of Competing Interest The authors declare no competing financial interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

M2 polarized tumor-associated macrophages (TAMs) have a multifunctional role in cancer initiation, progression, metastasis, and contribute to chemotherapeutic resistance. Therefore, identifying M2 polarized TAMs is a potential target for cancer therapeutic intervention. The underlying mechanism that target the TAMs M2 polarized macrophages remains primarily uncharacterized; however, only a few compounds have been identified that inhibit TAMs M2 polarized macrophages. In this research, we investigated that lapatinib could effectively suppress the expression of IL _ 13-induced M2 polarized macrophages surface markers i.e., CD163 and CD206, and downregulation of M2 genes such as Fizz1, Mrc1, Arg1, IL-10, Ym1, nd CCL2 in vitro. Moreover, lapatinib abrogated the M2 polarized macrophage-mediated cancer cells invasion and migration. Mechanistically, in our study, lapatinib inhibited IL-13 triggered STAT6 phosphorylation. Furthermore, in LLCs tumor model, lapatinib significantly reduced tumorigenesis, followed by the downregulation of percentages of M2 marker CD206 + and CD68 + in the tumor. This downregulation correlates with chemopreventive effect of lapatinib. All taken together, these results demonstrated that lapatinib effectively prevents the macrophage M2 polarization and indicates a potential mechanism for preventing the tumor growth via M2 polarized polarization intervention., Competing Interests: Conflict of interest statement No conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background: Metformin, a first-line oral anti-diabetic drug, has recently been reported to exert protective effect on various cardiovascular diseases. However, the potential role of metformin in ethanol-induced cardiomyocyte injury is still unknown. Therefore, this study was aimed to investigate the effect of metformin on ethanol-induced cardiomyocyte injury and its underlying mechanism., Methods and Results: H9c2 cardiomyocytes were exposed to ethanol for 24 h to establish an ethanol-induced cardiomyocyte injury model, and followed by treatment with metformin in the presence or absence of Lapatinib (an ErbB2 inhibition). CCK8 and LDH assays demonstrated that metformin improved cell viability in cardiomyocytes exposed to ethanol. Furthermore, metformin suppressed cardiomyocyte apoptosis and reduced the expressions of apoptosis-related proteins (Bax and C-CAS-3). In addition, our results showed that metformin activated the AKT/Nrf2 pathway, and then promoted Nrf2 nuclear translocation and the transcription of its downstream antioxidant genes (HO-1, CAT and SOD2), thereby inhibiting oxidative stress. Interestingly, we found that ErbB2 protein expression was significantly inhibited in ethanol-treated cardiomyocytes, which was markedly reversed by metformin. In contrast, Lapatinib largely abrogated the activation of AKT/Nrf2 signaling by metformin, accompanied by the increases in oxidative stress and cardiomyocyte apoptosis, indicating that metformin prevented ethanol-induced cardiomyocyte injury in an ErbB2-dependent manner., Conclusion: In summary, our study provides the first evidence that metformin protects cardiomyocyte against ethanol-induced oxidative stress and apoptosis by activating ErbB2-mediated AKT/Nrf2 signaling. Thus, metformin may be a potential novel treatment approach for alcoholic cardiomyopathy., (© 2023. The Author(s), under exclusive licence to Springer Nature B.V.)

As breast cancer cells transition from letrozole-sensitive to letrozole-resistant, they over-express epidermal growth factor receptor (EGFR), mitogen-activated protein kinase (MAPK), and human epidermal growth factor receptor 2 (HER2) while acquiring enhanced motility and epithelial-to-mesenchymal transition (EMT)-like characteristics that are attenuated and reversed by glyceollin treatment, respectively. Interestingly, glyceollin inhibits the proliferation and tumor progression of triple-negative breast cancer (TNBC) and estrogen-independent breast cancer cells; however, it is unlikely that a single phytochemical would effectively target aromatase-inhibitor (AI)-resistant metastatic breast cancer in the clinical setting. Since our previous report indicated that the combination of lapatinib and glyceollin induced apoptosis in hormone-dependent AI-resistant breast cancer cells, we hypothesized that combination therapy would also be beneficial for hormone independent letrozole-resistant breast cancer cells (LTLT-Ca) compared to AI-sensitive breast cancer cells (AC-1) by decreasing the expression of proteins associated with proliferation and cell cycle progression. While glyceollin + lapatinib treatment caused comparable inhibitory effects on the proliferation and migration in both cell lines, combination treatment selectively induced S and G2/M phase cell cycle arrest of the LTLT-Ca cells, which was mediated by decreased cyclin B1. This phenomenon may represent a unique opportunity to design novel combinatorial therapeutic approaches to target hormone-refractory breast tumors.

The downregulation of Pleckstrin Homology-Like Domain family A member 1 (PHLDA1) expression mediates resistance to targeted therapies in receptor tyrosine kinase-driven cancers. The restoration and maintenance of PHLDA1 levels in cancer cells thus constitutes a potential strategy to circumvent resistance to inhibitors of receptor tyrosine kinases. Through a pharmacological approach, we identify the inhibition of MAPK signalling as a crucial step in PHLDA1 downregulation. Further ChIP-qPCR analysis revealed that MEK1/2 inhibition produces significant epigenetic changes at the PHLDA1 locus, specifically a decrease in the activatory marks H3Kme3 and H3K27ac. In line with this, we show that treatment with the clinically relevant class I histone deacetylase (HDAC) inhibitor 4SC-202 restores PHLDA1 expression in lapatinib-resistant human epidermal growth factor receptor-2 (HER2) + breast cancer cells. Critically, we show that when given in combination, 4SC-202 and lapatinib exert synergistic effects on 2D cell proliferation and colony formation capacity. We therefore propose that co-treatment with 4SC-202 may prolong the clinical efficacy of lapatinib in HER2 + breast cancer patients.