Lapatinib Research Articles (Page 1)

Breast cancer is the most commonly diagnosed cancer and the leading cause of cancer mortality in females. Approximately 20-30% of patients with advanced breast cancer develop brain metastasis. Often, brain metastatic breast cancer (BMBC) exhibits a nonproliferative (dormant) phenotype and therapy resistance due to the unfavorable organ microenvironment. However, the mechanisms by which dormant BMBC micrometastases develop resistance to treatment remain unknown. In the current work, we utilized hyaluronic acid (HA) hydrogels to study the relationship between matrix rigidity-induced dormancy and the drug resistance of BMBC spheroids. BMBC spheroids were cultured on soft (∼0.4 kPa) or stiff (∼4.5 kPa) HA hydrogels, known to induce dormant versus proliferative states, and their response to Paclitaxel (PTX) or Lapatinib (LAP) treatment was measured. Spheroids on soft HA hydrogels were resistant to PTX or LAP treatment. Conversely, spheroids on stiff HA hydrogels were responsive to PTX or LAP treatment. Moreover, the resistance to therapy was mediated by glucocorticoid receptor (GR) signaling via serum/glucocorticoid-regulated kinase 1 (SGK-1) and RANBP1 in triple-negative BMBC cells and β-catenin and GSK-3β in human epidermal growth factor receptor 2 positive (HER2+) BMBC cells. Further, SGK1 inhibition alleviated drug resistance and resulted in response to treatment. Overall, this work provides evidence for dormancy associated drug resistance through GR signaling in BMBC spheroids.

Current research is focused on developing phospholipid-based nanolipidic carrier (NLC) to deliver lapatinib (LNB) and imatinib (INB) to MDA-MB-231 breast cancer cells and an in vivo mammary tumor model. Breast cancer (BC) was induced in female rats via the chemical carcinogen 7, 12-dimethylbenz(a)anthracene (DMBA). The dual drug-loaded phospholipid-based NLC were made via a hot microemulsion process. The developed NLC were also characterized, and tested in vitro, in vivo, and in a preclinical setting in a DMBA-induced rat model. The dual drug-loaded phospholipid NLC exhibited favorable nanometric size (279.7 nm, PDI 0.323), high entrapment efficiency (94.21%), and robust loading capacity (13.11%). It achieved biphasic drug release (52.67% at 4 h; 92.12% cumulative), potent cytotoxicity with maximal IC₅₀ reduction at 48 h, and maintained stability under accelerated conditions. In vivo, it significantly reduced tumor burden, normalized hematological and biochemical markers, and demonstrated therapeutic efficacy in DMBA-induced breast cancer, highlighting its translational potential. The dual drug-loaded NLC not only achieved high entrapment efficiency but also enhanced cytotoxicity against MDA-MB-231 cells and significantly reduced tumor progression. The developed lipid-based nanocarrier system demonstrates strong potential as a targeted platform for the co-delivery of kinase inhibitors, addressing the therapeutic limitations associated with monotherapy and conventional drug formulations.

Pharmacokinetic limitations of lapatinib (LPT) often result in low patient compliance and premature therapeutic discontinuation. Complex, long-acting formulations of the LPT are also challenging to develop due to the high crystallinity of the drug, limiting its solubility even in lipidic media. This manifests in the low loading of LPT reported for most of the attempted advanced delivery systems, whereas a few high-loading formulations have shown very fast release. In this work, we hypothesized that rich aromatic rings of LPT can be leveraged to form supramolecular π-π interactions with suitable carriers. Functionalized graphene oxide (GO) derivatives, which are finding increasing application in cancer drug delivery, poly(ethylene glycol)-GO (PEG-GO) and L-lactic acid-GO (LA-GO), were selected as carriers because of the potential of GO to form π-π stacking interactions. Bathochromic shifts of around 40 nm of both the absorption maxima of LPT (261 and 294 nm to 301 and 328 nm), along with peak broadening caused by vibronic coupling between drug and carrier, indicated strong π-π interaction in LPT-PEG-GO. In LPT-LA-GO, significant peak disruption with small peak shifts indicated a putatively weaker π-π association. The ID:IG ratio examined by Raman spectroscopy showed a reduction to 0.82 and 0.50 in LPT-PEG-GO and LPT-LA-GO, respectively, from ∼1.30 before drug loading, supporting absorption spectroscopy observations. These underlying interactions translated into loading efficiencies of 48.7% in LPT-PEG-GO and 44.3% in LPT-LA-GO, which are higher than current literature values. Further, LPT-PEG-GO demonstrated 82% zero-order controlled release up to 168 h at pH 5.0 but only 20% release at pH 7.4. In the case of LPT-LA-GO, an initial 48 h higher dissolution rate of LPT was observed, followed by sustained release up to 168 h with almost 78% release at pH 5.0 and 14% release at pH 7.4. In both LPT-PEG-GO and LPT-LA-GO, the LPT release concentration was in the order of 5-15 μM from a 1 mg/mL formulation, showing the dose can be suitably reduced to maintain desired IC50 values on cancer cell lines. Higher cytotoxicity of LPT-PEG-GO and LPT-LA-GO was observed by MTT assay in MDAMB-231 (breast cancer) and HEK293 (noncancerous) cell lines. Percent cell viability was found to be 69 and 72% (in the case of MDAMB-231 cell line), and 94 and 93% (in the case of HEK 293) of control for LPT-PEG-GO and LPT-LA-GO containing 1 μM loaded LPT, respectively. The cytotoxicity effect was corroborated by cellular uptake and apoptosis studies. In conclusion, functionalized GO demonstrates significant improvement in the loading capacity of LPT through supramolecular interactions, while its release profile can be modulated by GO functionalization, presenting a promising delivery system for enhancing the therapeutic efficacy in the treatment of metastatic breast cancer.

Abstract Metastatic disease is responsible for over 90% of cancer-related deaths, with breast cancer patients exhibiting a survival rate of only 5% once bone metastases develop. Traditional 2D in vitro models often fail to accurately replicate the tumor microenvironment (TME) and drug responses observed in vivo. To address these limitations, we utilized advanced 3D in vitro models to better simulate primary and metastatic tumors, enabling the study of cancer-stromal interactions and drug efficacy. Patient-derived cancer cells (PDCs) from three molecular subtypes of breast cancer were used to model both primary tumors (using a hanging drop system) and bone metastases (using a bioengineered bone-mimetic scaffold). Stromal components, including endothelial cells (ECs), macrophages, and cancer-associated fibroblasts (CAFs), were co-cultured with PDCs to mimic TME more closely. As expected, drug sensitivity profiles generated within 48 hours revealed significant differences between 2D and 3D models when treated with paclitaxel (PTX), doxorubicin (DOX), lapatinib (LAPA), and 4-hydroxy tamoxifen (4-OH TAM). PDCs at bone metastatic sites exhibited higher survival rates post-treatment, as indicated by elevated BCL2 and Ki67 expression and lower CAS9 expression compared to primary tumor sites. This suggests site-specific resistance mechanisms, emphasizing that bone metastases may require higher drug doses to achieve comparable efficacy. Stromal interactions significantly influenced angiogenic capacity. While drug treatments substantially altered network formation when ECs and PDCs were cultured together, the presence of CAFs produced opposing effects. These findings underscore the complexity of bone TME and suggest that higher drug doses or combination therapies may be necessary to effectively target metastatic tumors. Additionally, we are incorporating macrophages into the TME in ongoing experiments to further elucidate their contributions to angiogenesis and therapeutic resistance. Moving forward, we will employ single-cell sequencing of 3D models to investigate tumor heterogeneity and refine dose-specific treatments, advancing precision medicine strategies to combat metastasis and improve patient outcomes. This work is currently in progress. Our single-cell sequencing data aims to reveal distinct gene expression differences between primary tumor sites and metastatic sites within the tumor microenvironment. By identifying unique gene expression profiles in cancer cells, stromal cells, and immune cells at each site, we aim to uncover critical pathways driving metastasis. These findings will guide the development of targeted therapies that specifically address metastatic tumors, thereby preventing metastasis and minimizing off-target effects. Citation Format: Shrinwanti Ghosh, Sangdeuk Ha, Anu Gaba, Kalpana Katti, Jiha Kim. 3D in vitro models for identifying primary vs. metastatic tumors in targeted breast cancer treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2692.

Lapatinib (LAP), a dual inhibitor targeting ErbB1 and ErbB2 tyrosine kinases, demonstrates efficacy in treating ErbB2-positive breast cancer. However, its clinical use is hindered by the occurrence of associated diarrhoea. ErbB1 is expressed in the intestine; leading to the hypothesis that lapatinib inhibits normal ErbB1 function, causing diarrhoea. This study explores the potential role of ErbB1 inhibition in the mechanism of lapatinib-induced diarrhoea. Caco-2 intestinal monolayers were treated with LAP alone and in combination with recombinant epidermal growth factor (LAP+rEGF). The integrity of the Caco-2 monolayer was evaluated by measuring transepithelial electrical resistance (TEER) of the Caco-2 monolayer and Lucifer yellow paracellular transport. Changes in tight junction proteins (TJPs) claudin-1, occludin and ZO-1 were assessed through qPCR and immunofluorescence staining, while the expression levels of inflammatory cytokines TNF-α, IL-1β, and IL-6 were determined using qPCR. At 96 hours, LAP treatment resulted in a significant reduction in TEER compared to the untreated control monolayer (p < 0.05). Although not significantly different from the control group, the LAP group exhibited higher Lucifer yellow permeability. LAP suppressed mRNA and protein expression of TJPs, with cotreatment of rEGF mitigating LAP inhibition significantly (p < 0.05). No significant changes were observed in the mRNA expression levels of inflammatory cytokines in the LAP group. However, treatment with rEGF increased IL-6 mRNA expression significantly (p < 0.01). Lapatinib increased Caco-2 intestinal monolayer permeability and reduced tight junctions by inhibiting ErbB1, suggesting a mechanism of lapatinib-induced diarrhoea.

Doxorubicin (DOX) and lapatinib (LAP) have been reported to cause liver toxicity. The roles of mitochondrial and cellular responses in DOX and LAP mediated-hepatotoxicity have not been investigated with or without quercetin (QUE) in HepG2 cells sensitive to mitochondrial damage (high-glucose or galactose media) in addition to in silico studies. Our results revealed that cytosolic pathways might play role a in DOX-induced cytotoxicity rather than mitochondria. QUE exacerbated DOX-induced ATP depletion in both environments. Our data also indicated that cytosolic and mitochondrial pathways might play a role in LAP-induced cytotoxicity. Incubating QUE with LAP increased ATP levels in high-glucose media. Therefore, QUE might have protective effect against LAP-induced cytotoxicity resulting from cytosolic pathways. The findings from in vitro experiments that QUE increased DOX or LAP-induced mitochondrial dysfunction were confirmed by the results from in silico studies indicating that QUE incubated with LAP or DOX might increase mitochondrial dysfunction.

Abstract Breast cancer is the most prevalent form of cancer, representing 12.5% of all cancer cases diagnosed worldwide. Breast cancer cells can metastasize to distant organs (i.e., brain) and remain dormant for extended periods of time. This aspect makes it very difficult to treat these cells as they exhibit reduced growth as well as resistance to therapy. Despite advances in our understanding of breast cancer metastasis, the specific mechanisms that enable dormant cancer cells to resist therapeutics, particularly in brain metastatic breast cancer (BMBC), remain unclear. Herein, we employed brain tissue mimetic hyaluronic acid (HA) hydrogels of varying stiffness (i.e., ~0.4 kPa vs. ~4.5 kPa) to investigate the response to chemo or targeted therapy in dormant versus proliferative BMBC cells. It was revealed that BMBC cells grown on soft HA hydrogels (~0.4 kPa) displayed a non-proliferative (i.e., dormant) phenotype and exhibited resistance to Paclitaxel (PTX) or Lapatinib (LAP). However, BMBC cells grown on stiff HA hydrogels (~4.5 kPa) displayed a proliferative phenotype and sensitivity to PTX or LAP. Furthermore, we found that resistance to therapy was due to the enhanced expression of the serum/glucocorticoid regulated kinase 1 (SGK1) gene, mediated, in part, via the p38 mitogen-activated protein kinase (MAPK) pathway. Consequently, SGK1 inhibition using a SGK inhibitor in BMBC cells cultured on soft HA hydrogels resulted in a dormant-to-proliferative switch as well as response to PTX or LAP. In sum, our study demonstrated that matrix stiffness plays a major role in the dormancy-associated therapy response, mediated, in part, via the p38/SGK1 pathway.

Enhanced antitumor activity of lapatinib against triple-negative breast cancer via loading in human serum albumin

LC-HRMS-based global metabolomics profiling unravels the distinct metabolic signature of lapatinib-resistant and trastuzumab-resistant HER2+ breast cancer cells

INPP4B suppresses HER2-induced mesenchymal transition in HER2+ breast cancer and enhances sensitivity to Lapatinib

pH-responsive drug-loaded peptides enhance drug accumulation and promote apoptosis in tumor cells

Abstract Objectives: Endocrine therapy resistance is a significant clinical challenge for patients with estrogen receptor (ER)-positive breast cancer. Dysregulation of the ER and ERBB signaling pathways plays a key role in endocrine therapy resistance. However, it is unclear how these pathways are integrated during resistance development. SMAD4 is involved in multiple stages of tumorigenesis, but its role in endocrine resistance development remains elusive. Here, we aimed to investigate the role of SMAD4 in the development of acquired endocrine therapy resistance in ER-positive breast cancer. Methods: CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) screening was conducted to identify genes involved in regulating the sensitivity of T47D cells to 4-hydroxytamoxifen (OHT). Bioinformatics analysis was performed to explore the clinical significance of SMAD4. The differential expression of SMAD4 in cells before and after endocrine treatment was assessed by RT-qPCR and immunoblotting. Loss-/gain-of-function assays were conducted to validate the phenotype. RNA-seq and phenotype rescue experiments were used to explore the underlying mechanisms. Drug combination experiments were performed to assess the therapeutic effect on SMAD4-depleted cells. Results: CRISPR screening identified SMAD4 as a key determinant of endocrine therapy resistance. Bioinformatic analysis showed that SMAD4 expression was downregulated in breast cancer tissues and that low expression was associated with poor patient prognosis. Differential expression analysis after endocrine therapy treatment showed that endocrine therapy downregulated the expression of SMAD4. In vitro and in vivo models further demonstrated that SMAD4 downregulation leads to endocrine therapy resistance. Transcriptome sequencing analysis identified that the ER, ERBB and PI3K/Akt/mTOR signaling pathways were aberrantly activated upon SMAD4 depletion. Further analysis revealed that the PI3K/Akt/mTOR pathway may contribute to the regulation of ERBB on ER signaling to some extent. The aberrant activation of autophagy in phenotype rescue experiments was found to reduce the rescue effect of the combination of 4-hydroxytamoxifen (OHT) and lapatinib (LAPA). Finally, drug combination experiments verified that the combined use of OHT, LAPA and hydroxychloroquine (CQ) produced a synergistic effect in SMAD4-depleted cells. Conclusions: Taken together, our findings demonstrate that SMAD4 plays a crucial role in endocrine therapy resistance and suggest a reasonable treatment strategy for ER-positive breast cancer patients who are resistant to endocrine therapy. Citation Format: Kang Li, Dan Shu, Han Li. SMAD4 depletion contributes to endocrine therapy resistance by ERBB signaling in HR+HER2- breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-23-11.

Lapatinib combined with doxorubicin causes dose-dependent cardiotoxicity partially through activating the p38MAPK signaling pathway in zebrafish embryos

Unveiling the therapeutic prospects of EGFR inhibition in rotenone-mediated parkinsonism in rats: Modulation of dopamine D3 receptor

Anticancer agents are playing an increasing role in the treatment of gastric cancer (GC); however, novel anticancer agents have not been fully developed. Therefore, it is important to investigate compounds that improve sensitivity to the existing anticancer drugs. We have reported that pterostilbene (PTE), a plant stilbene, enhances the antitumor effect of low doses of sunitinib in gastric cancer cells accumulating mitochondrial iron (II) (mtFe) at low doses. In this study, we investigated the relationship between the mtFe deposition and the synergistic effect of PTE and different anticancer drugs. For this study, we used 5-fluorouracil (5FU), cisplatin (CPPD), and lapatinib (LAP), which are frequently used in the treatment of GC, and doxorubicin (DOX), which is known to deposit mtFe. A combination of low-dose PTE and these drugs suppressed the expression of PDZ domain-containing 8 (PDZD8) and increased mtFe accumulation and mitochondrial H2O2. Consequently, reactive oxygen species-associated hypoxia inducible factor-1α activation induced endoplasmic reticulum stress and led to apoptosis, but not ferroptosis. In contrast, 5FU and CDDP did not show the same changes as those observed with PTE and DOX or LAP, and there was no synergistic effect with PTE. These results indicate that the combination of PTE with iron-accumulating anticancer drugs exhibits a strong synergistic effect. These findings would help in developing novel therapeutic strategies for GC. However, further clinical investigations are required.

Synthesis and in vitro evaluation of 99mTc radiolabeled lapatinib (LPT) and its PLGA formulation

Cancer is considered a silent killer. The complexity of cancer makes it earn that title. So far there are only a few approaches to treat cancer. Among them, chemotherapy is considered the best approach. Many chemotherapeutical compounds are commercially available in the market. Among them, doxorubicin (DOX) and lapatinib (LAP) are considered blockbuster molecules. However, DOX suffers from poor bioavailability and exhibits cardiotoxicity. Interestingly, a fixed dose combination of DOX and LAP significantly decreases the cardiotoxic effect of DOX. To enhance the oral bioavailability of DOX and to avail the synergistic effect of LAP, many formulations have been made. To quantify both compounds in any formulation or biological matrix, an Liquid chromatography-Mass Spectrometry (LC-MS) method is required. In this present study, a simple and rapid Ultra High-Performance Liquid Chromatography - Heated Electron Spray Ionization - Mass Spectrometry (UHPLC-HESI-MS) bioanalytical method was developed. The developed method was validated as per the regulatory guidelines. The validated bioanalytical method had a lower limit of quantification of 0.75ng. A simple protein precipitation technique was optimized to extract the compounds from the rat plasma. All the validation parameters were found to be within the limits as per the regulatory guidelines. A novel and rapid analytical method was successfully developed and validated. This developed method can be used to quantify the DOX and LAP in any formulation and biological matrix.

Co-delivery of lapatinib and 5-fluorouracil transfersomes using transpapillary iontophoresis for breast cancer therapy

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. 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. 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.

Lapatinib ditosylate rescues motor deficits in rotenone-intoxicated rats: Potential repurposing of anti-cancer drug as a disease-modifying agent in Parkinson's disease