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Introduction: Modern cancer treatment strategies aim at achieving cancer remission by using targeted and personalized therapies, as well as harnessing the power of the immune system to recognize and eradicate the cancer cells. To overcome a relatively short-lived response due to resistance to the administered drugs, combination therapies have been pursued. Objective: The objective of this study was to use high-throughput data generation technologies such as mass spectrometry and proteomics to investigate the broader implications, and to expand the outlook, of such therapeutic approaches. Specifically, we investigated the systems-level response of a breast cancer cell line model to a mixture of kinase inhibitors that has not been adopted yet as a standard therapeutic regime. Methods: Two critical pathways that sustain the growth and survival of cancer cells, EGFR and PI3K/AKT, were inhibited in SKBR3/HER2+ breast cancer cells with Lapatinib (Tyr kinase inhibitor) and Ipatasertib (Ser/Thr kinase inhibitor), and the landscape of the affected biological processes was investigated with proteomic technologies. Results: Over 800 proteins matched by three unique peptide sequences were affected by exposing the cells to the drugs. The work corroborated the antiproliferative activity of Lapatinib and Ipatasertib and uncovered a range of impacted cancer-supportive hallmark processes, among which immune response, adhesion, and migration emerged as particularly relevant to the ability of drugs to effectively suppress the proliferation and dissemination of cancer cells. Changes in the expression of key cancer drivers such as oncogenes, tumor suppressors, EMT and angiogenesis regulators underscored the inhibitory effectiveness of drugs on cancer proliferation. The supplementation of Lapatinib with Ipatasertib further affected additional transcription factors and proteins involved in gene expression, trafficking, DNA repair, and development of multidrug resistance. Furthermore, over fifty of the impacted proteins represent approved or investigational targets in the DrugBank database, which through their protein-protein interaction networks can inform the selection of effective therapeutic partners. Conclusion: Altogether, the exposure of SKBR3/HER2+ cells to Lapatinib and Ipatasertib kinase inhibitors uncovered a broad plethora of yet untapped opportunities that can be further explored for enhancing the anti-cancer effects of each drug as well as of many other multi-drug therapies that target the EGFR/ ERBB2 and PI3K/AKT pathways. [ABSTRACT FROM AUTHOR]

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 (IC50) 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. [ABSTRACT FROM AUTHOR]

Different targeted therapy options exist for treating HER2-positive metastatic breast cancer patients. This study evaluated the efficacy and tolerability of the lapatinib plus capecitabine combination after TDM-1 in HER2-positive metastatic breast cancer patients. We retrospectively evaluated the HER2-positive metastatic breast cancer patients' data. The patients who progressed after trastuzumab-based chemotherapy and TDM-1 were included in the study. We used the Kaplan–Meier for survival analysis. Eighteen patients were involved in the study. The average age was 48 (range 31–65). De novo metastatic patient's number was 5 (27.8%). The most common metastatic sites were liver (50%), lung (44.4%), and brain (44.4%), respectively. All patients were previously treated with trastuzumab + chemotherapy and TDM-1. Also, seven (38.9%) patients received hormonotherapy and twelve (66.7%) patients received palliative radiotherapy. The complete response ratio was 5.6%, partial response 11.8%, and stable response 29.4%. Median progression-free survival was found as 5.5 (95% CI, 3.2–7.7) months. The hematological and non-hematological toxicity ratio was 41.2% and 52.9%, respectively. Grade 3–4 toxicity (diarrhea, anemia, and mucositis) was observed in four (22.2%) patients. The median OS duration was 8.2 months (95% CI, 4.3–12.0). Treatment options are limited in heavily pretreated HER2-positive breast cancer patients. Despite a small number of patients, this study showed that the lapatinib plus capecitabine combination was effective and well-tolerated in heavily pretreated HER2-positive breast cancer patients after TDM-1. [ABSTRACT FROM AUTHOR]

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.

Abstract Despite clinical benefits of tyrosine kinase inhibitors (TKIs) in cancer, most tumors can reactivate proliferation under TKI therapy. Here we present transcriptional profiling of HER2+ breast cancer cells transitioning from dormant drug tolerant cells to re-proliferating cells under continuous HER2 inhibitor (HER2i) therapy. Focusing on phosphatases, expression of dual-specificity phosphatase DUSP6 was found inhibited in dormant cells, but strongly induced upon regrowth. DUSP6 expression also selectively associated with poor patient survival in HER2+ breast cancers. DUSP6 overexpression conferred apoptosis resistance, whereas its pharmacological blockade prevented therapy tolerance development under HER2i therapy. DUSP6 targeting also synergized with clinically used HER2i combination therapies. Mechanistically DUSP6 is a positive regulator of HER3 expression, and its impact on HER2i tolerance was mediated by neuregulin-HER3 axis. In vivo, genetic targeting of DUSP6 reduced tumor growth in brain metastasis model, whereas its pharmacological targeting induced synthetic lethal therapeutic effect in combination with HER2i. Collectively this work demonstrates that DUSP6 drives escape from HER2i-induced dormancy, and that DUSP6 is a druggable target to overcome HER3-driven TKI resistance.

Background: The therapeutic efficacy of an active Pharmaceutical ingredient depends on its solubility in body fluids. The low bioavailability of nearly 90% of new active Pharmaceutical ingredients and 40% of the existing molecules is attributed to their poor solubility. The current study aimed to improve the oral bioavailability of lapatinib by designing and optimizing nanostructured lipid carriers for it. Materials and Methods: The formulation utilized the microemulsion technique as a method of preparation and the Box Behnken design was used for optimization. Results: The average particle size, drug entrapment, and release, in percentages, were observed to be 237.09 nm, 72.32%, and 74.66% respectively. Conclusion: In vitro studies proved that NSLC significantly releases a drug more than the marketed formulation. [ABSTRACT FROM AUTHOR]

Despite clinical benefits of tyrosine kinase inhibitors (TKIs) in cancer, most tumors can reactivate proliferation under TKI therapy. Here we present transcriptional profiling of HER2+ breast cancer cells transitioning from dormant drug tolerant cells to re-proliferating cells under continuous HER2 inhibitor (HER2i) therapy. Focusing on phosphatases, expression of dual-specificity phosphatase DUSP6 was found inhibited in dormant cells, but strongly induced upon regrowth. DUSP6 expression also selectively associated with poor patient survival in HER2+ breast cancers. DUSP6 overexpression conferred apoptosis resistance, whereas its pharmacological blockade prevented therapy tolerance development under HER2i therapy. DUSP6 targeting also synergized with clinically used HER2i combination therapies. Mechanistically DUSP6 is a positive regulator of HER3 expression, and its impact on HER2i tolerance was mediated by neuregulin-HER3 axis. In vivo, genetic targeting of DUSP6 reduced tumor growth in brain metastasis model, whereas its pharmacological targeting induced synthetic lethal therapeutic effect in combination with HER2i. Collectively this work demonstrates that DUSP6 drives escape from HER2i-induced dormancy, and that DUSP6 is a druggable target to overcome HER3-driven TKI resistance. Synopsis: Resistance to HER2 inhibitors (HER2i) is common in patients with HER2+ breast cancer and the HER3 signaling pathway is an important mediator of this therapy resistance. This study reveals oncogenic phosphatase DUSP6 as a critical mediator of development of HER2i tolerance via regulation of HER3. DUSP6 has key roles in the emergence of HER2+ drug-tolerant expanding persister (DTEP) cells and in resistance to HER2i therapies. DUSP6 inhibits HER2i-induced apoptosis, and its blockade increases therapeutic sensitivity in vitro and in vivo. DUSP6 determines sensitivity to HER2-directed therapies via regulation of HER3 receptor whereas NRG-activated HER3 drives DUSP6 expression. DUSP6 is a promising small molecule inhibitor target protein for patients with HER2i resistant tumors or HER2+ brain metastasis. Resistance to HER2 inhibitors (HER2i) is common in patients with HER2+ breast cancer and the HER3 signaling pathway is an important mediator of this therapy resistance. This study reveals oncogenic phosphatase DUSP6 as a critical mediator of development of HER2i tolerance via regulation of HER3. [ABSTRACT FROM AUTHOR]

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. Article highlights α-D-tocopherol succinate (vitamin E) was conjugated to human serum albumin (HSA). The HSA-VE conjugate formed nanoparticles (NPs) by self-assembly without any external cross-linker and loaded Lapatinib (Lapa). The NPs were characterized thoroughly. Time-dependent uptake of NPs was observed in tested sensitive and resistant human breast cancer cell lines (MCF-7). The nanomedicine displayed enhanced cytotoxicity in breast cancer cell lines compared with free drugs at higher concentrations. Lapa@HSA(VE) NPs caused significantly higher reactive oxygen species (ROS) generation and mitochondrial depolarization in tested breast cancer cell lines compared with free Lapa. In vivo pharmacokinetic data showed sustained drug release from nanoformulation with decreased systemic clearance, and in vivo, toxicity study revealed that the nanoformulation considerably reduced hepatotoxicity compared with free Lapa. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Lung cancer is one of the most acute types of cancer that cannot be easily treated with current treatments. In this study, Co3O4 nanoparticles were synthesized and functionalized by glucose and conjugated with Lapatinib. Physicochemical properties of the Co3O4@Glu- Lapatinib nanoparticles were characterized by FT-IR, XRD, EDS-mapping, SEM, TEM, DLS, and zeta potential analysis. The viability of the lung cancer and lung fibroblast cells treated with different concentrations of Co3O4@Glu-Lapatinib, Lapatinib and Co3O4 were investigated by MTT assay. The effect of the nanoparticles on cell cycle and cell apoptosis was determined by flow cytometry and Hoechst staining assays. The relative expression of the CASP8, mTOR1, and MAPK1 genes was also quantified using a real-time PCR assay. The synthesized nanoparticles were spherical, with a size of 29–64 nm, zeta potential of 36.8 mV, DLS size of 323 nm, and without elemental impurities. Co3O4@Glu-Lapatinib nanoparticles showed concentration-dependent toxicity on the studied cell lines and were significantly more toxic for the breast cancer cells than breast fibroblast cells with IC50 values of 89 and 178 µg/ml, respectively. Treating cancer cells with Co3O4@Glu-Lapatinib nanoparticles increased cell cycle arrest at the sub-G1 and G0/G1 phases and increased the percentage of apoptotic cells from 0.83 to 88.75%. Furthermore, treating cancer cells with the nanoparticles led to overexpression of the CASP8 and MAPK1 genes by 4.48 and 3.4 folds, respectively, while down-regulated the mTOR1 gene by 0.62 folds. Co3O4@Glu-Lapatinib nanoparticles can exert antiproliferative effects on lung cancer cells through the inhibition of growth signaling factors and activation of apoptogenic mechanisms. [ABSTRACT FROM AUTHOR]

Dual inhibitors of HER2 and EGFR, such as lapatinib, have shown significant efficacy for the therapy of HER2-positive breast cancer. Previous experiments showed that in cell cultures, the efficacy of lapatinib was significantly reduced by exposure to human serum and human epidermal growth factor (EGF). At the proteomic and transcriptomic levels, we examined the changes in the HER2-positive breast cancer cell line SK-BR-3 profiles upon treatment with lapatinib, either alone or in combination with human serum or EGF. Proteomic profiling revealed 350 differentially expressed proteins (DEPs) in response to lapatinib treatment at concentrations that induced cell growth arrest. Addition of human serum or EGF in combination with lapatinib prevented cell growth inhibition, and this combination treatment returned the expression of ∼93% of DEPs to drug-free levels for both human serum and EGF. Gene ontology enrichment and OncoboxPD pathway activation level analysis showed that lapatinib addition influenced mostly common functional processes revealed in RNA- and protein-based assays. However, a specific feature was observed at the proteome level: addition of lapatinib increased the expression of proteins associated with mitochondrial function and cellular respiration. This feature was not observed when using RNA sequencing data for the same experiments. However, it is consistent with the results of the resazurin test, which showed a 1.8-fold increase in SK-BR-3 cellular respiration upon exposure to lapatinib. Thus, we conclude that enhanced cellular respiration is a novel additional mechanism of action of lapatinib on HER2-positive cancer cells.

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Lapatinib plus whole brain radiation therapy (WBRT) or stereotactic radiosurgery (SRS) was hypothesized to improve the 12-week intracranial complete response (CR) rate compared with either option of radiation therapy (RT) alone for patients with brain metastases (BM) from human epidermal growth factor receptor 2–positive (HER2+) breast cancer. This study included patients with HER2+ breast cancer with ≥1 measurable, unirradiated BM. Patients were randomized to WBRT (37.5 Gy/3 wk)/SRS (size-based dosing) ± concurrent lapatinib (1000 mg daily for 6 weeks). Secondary endpoints included objective response rate (ORR), lesion-specific response, central nervous system progression-free survival, and overall survival. From July 2012 to September 2019, 143 patients were randomized, with 116 analyzable for the primary endpoint. RT + lapatinib did not improve 12-week CR (0% vs 6% for RT alone, 1-sided P =.97), or ORR at 12 weeks. At 4 weeks, RT + lapatinib showed higher ORR (55% vs 42%). Higher graded prognostic assessment and ≤10 lesions were associated with higher 12-week ORR. Grade 3 and 4 adverse event rates were 8% and 0% for RT and 28% and 6% for RT + lapatinib. The addition of 6 weeks of concomitant lapatinib to WBRT/SRS did not improve the primary endpoint of 12-week CR rate or 12-week ORR. Adding lapatinib to WBRT/SRS showed improvement of 4-week ORR, suggesting a short-term benefit from concomitant therapy. [ABSTRACT FROM AUTHOR]

This article explores the potential of inhibiting autophagy, a cellular process that breaks down and recycles damaged components, to improve the effectiveness of the cancer drug lapatinib in treating breast cancer brain metastases. The study found that inhibiting autophagy through genetic manipulation or using the drug hydroxychloroquine enhanced the anticancer activity of lapatinib and reduced the number of brain metastases in animal models. The combination treatment also extended animal survival compared to using lapatinib alone. The authors suggest that targeting autophagy could be a promising therapeutic approach for breast cancer brain metastases and call for further research in this area. [Extracted from the article]

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. [ABSTRACT FROM AUTHOR]

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 EC50 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Lapatinib is an orally administered tyrosine kinase inhibitor used to treat human epidermal growth factor receptor 2 (HER2) -overexpressing breast cancers in humans. Recently, the potential of lapatinib treatment against canine urothelial carcinoma or feline mammary tumor was investigated. However, the pharmacokinetic studies of lapatinib in dogs and cats are not well-defined. In the present study, the pharmacokinetic characteristics of lapatinib in both cats and dogs after a single oral administration at a dose of 25 mg/kg were compared with each other. Lapatinib was administered orally to four female laboratory cats and four female beagle dogs. Blood samples were collected over time, and the plasma lapatinib concentrations were analyzed by HPLC. Following a single dose of 25 mg/kg, the averaged maximum plasma concentration (Cmax) of lapatinib in cats was 0.47 μg/mL and achieved at 7.1 hr post-administration, while the Cmax in dogs was 1.63 μg/mL and achieved at 9.5 hr post-administration. The mean elimination half-life was 6.5 hr in cats and 7.8 hr in dogs. The average area under the plasma concentration-time curve of dogs (37.2 hr·μg/mL) was significantly higher than that of cats (7.97 hr·μg/mL). These results exhibited slow absorptions of lapatinib in both animals after oral administration. The Cmax observed in cats was significantly lower and the half-life was shorter than those observed in dogs. Based on these results, a larger dose or shorter dosing intervals might be recommended in cats to achieve similar plasma concentration as dogs. [ABSTRACT FROM AUTHOR]