lapatinib

Drug sensitivity to the HER2 kinase inhibitor lapatinib was characterized under conditions of monoculture and exposure to breast fibroblast-conditioned medium...Combination therapies targeting HER2 kinase and these fibroblast-induced signaling adaptations eliminates fibroblast-protected HER2+ breast cancer cells. The online version contains supplementary material available at 10.1007/s12195-024-00823-0.

The clinical success of KRASG12C inhibitors (G12Ci) including AMG510 and MRTX849 is limited by the eventual development of acquired resistance...We found the ferroptosis inducers including sorafenib and lapatinib stood out with an obvious growth inhibition in the G12Ci resistant cells...Ferroptosis induced by sulfasalazine (SAS) achieved obvious inhibition on the tumor growth of xenografts derived from AMG510-resistant KRASG12C-mutant cells. Collectively, our results suggest a novel therapeutic strategy to treat patients bearing G12Ci resistant cancers with ferroptosis inducers.

P1, N=29, Completed, National Cancer Institute (NCI) | Active, not recruiting --> Completed | Trial completion date: Oct 2025 --> Oct 2024

P3, N=608, Active, not recruiting, Daiichi Sankyo | Trial completion date: May 2025 --> Jul 2025

The selectivity index of 3f for EGFRT790M was 1.81 times more selective than that of lapatinib. In addition, 3e and 3f initiated cell cycle arrest at the G2/M and pre-G1 phases along with the downregulation of anti-apoptotic protein Bcl2 and the upregulation of pro-apoptotic proteins: p53, Bax, and caspases 3, 8, and 9. Further studies are recommended to evaluate animal models' promising anticancer activity and molecular mechanism of triazolo[3,4-a]isoquinoline derivatives 3e and 3f.

The National Comprehensive Cancer Network (NCCN) guidelines recommend the use of tyrosine kinase inhibitors (TKIs) lapatinib, neratinib, and tucatinib in co-administration with monoclonal antibodies or chemotherapy drugs and the antibody-drug conjugates (ADCs) trastuzumab-deruxtecan and trastuzumab-emtansine. In this review article, we discuss about the molecular and cellular features of the barriers located in the central nervous system and the pharmacological parameters found to be important in predicting BBB permeability in human normal brain and in the presence of brain metastases. Finally, we reported the clinical outcomes and intracranial response of patients with HER2-positive breast cancer with brain metastases treated with targeted TKIs and ADCs.

Moreover, cholesterol content in EVs was significantly higher in AnxA6-expressing cells than in AnxA6 downregulated cells and following chronic lapatinib induced upregulation of AnxA6...AnxA6 neutralizing antibodies strongly diminished the survival of AnxA6 low TNBC cells but had minimal effects on the survival of TNBC cells expressing relatively high levels of the protein. Together, these data suggest that AnxA6 facilitates the secretion of EVs and proinflammatory cytokines that may be critical for TNBC progression.

P1, N=29, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Oct 2024 --> Oct 2025

P3, N=545, Completed, Novartis Pharmaceuticals | Active, not recruiting --> Completed

The assessed compounds 7-17e showed considerable cytotoxic activity activities against HepG2 and MCF-7 with IC50 values of 0.137-0.332 and 0.164-0.583 μg mL-1, respectively, in comparison to erlotinib as the positive control, which showed an IC50 value of 0.308 and 0.512 μg mL-1, respectively...The results showed good IC50 values of 0.14 and 0.18 μM for compounds 8c and 12d, respectively, compared to lapatinib (IC50 value of 0.12 μM)...Compounds 17b, 17d and 17e displayed the most potent inhibitory activity, exhibiting 4-, 16- and 8-fold more activity, respectively, than the reference neomycin. Hence, we can conclude that the afforded compounds can be used as lead dual anticancer and antimicrobial candidates for future optimization.

Joint pathway enrichment analysis of LAP-resistant DEMs and differentially expressed genes (DEGs) showed enrichment in glutathione metabolism, while that of TRZ-resistance and DEGs showed enrichment in carbohydrate metabolism, namely pentose and glucuronate interconversions, starch and sucrose metabolism, and galactose metabolism. The findings from this study indicate considerable metabolic changes in LAP- and TRZ-resistant HCC1954 cells, which are crucial for understanding the resistance mechanisms and developing strategies to overcome these problems.

Biodistribution studies using technetium-99 m (99mTc) labeling revealed enhanced tumor targeting. These findings highlight the potential of HSA as a delivery vehicle for LAP, particularly in combination with anti-angiogenic agents like VGB3, offering a promising therapeutic strategy for TNBC.

With inhibitory (IC50) values of 71 and 31 nM, respectively, compound 5a proved to be the most effective dual-target inhibitor of EGFR and HER-2, outperforming the reference erlotinib (IC50 = 80 nM) as an EGFR inhibitor but falling short of the clinically used agent lapatinib (IC50 = 26 nM) as a HER2 inhibitor. The apoptotic potential activity of 5a was examined, and the findings demonstrated that 5a promotes apoptosis by activating caspase-3, 8, and Bax while simultaneously reducing the expression of the anti-apoptotic protein Bcl-2. The docking studies provided valuable insights into the binding interactions of compounds 3e and 5a with EGFR, effectively rationalizing the observed SAR trends.

In our institution, consecutive patients with Her2 positive metastatic breast cancer from 1 January 2014 to 31 December 2020 who could not afford trastuzumab, lapatinib or any other anti-Her2 agent were offered low-dose lapatinib, 500 mg daily with meal. Low-dose lapatinib is a regimen that offers an acceptable disease control rate. This strategy requires further exploration, particularly for the benefit of resource-limited areas.

With a longer follow-up, no significant improvement was observed in DFS in patients treated with dual anti-HER2 blockade with lapatinib + trastuzumab compared to trastuzumab alone. The 10-year survival rates for the combination group are consistent with other studies that have explored dual anti-HER2 therapy.

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.

Our results indicate an upregulation in the expression levels of HER2 and EGFR in certain common cancers, suggesting that lapatinib, in addition to breast cancer, could be considered for the treatment of these cancers. Furthermore, we demonstrated that some genes with increased expression in prevalent cancers and associated with poor prognosis have the potential to be modulated by lapatinib.

P2, N=647, Completed, National Cancer Institute (NCI) | Active, not recruiting --> Completed | Trial completion date: Dec 2024 --> Jul 2024

P3, N=545, Active, not recruiting, Novartis Pharmaceuticals | Trial completion date: Jan 2025 --> Oct 2024

Several TKIs, including lapatinib, neratinib, and tucatinib, have been developed and are currently used in clinical settings, often in combination with chemotherapy, endocrine therapy, or other targeted agents. TKIs have emerged as a promising therapeutic option for patients with breast cancer and hold potential for treating other breast cancer subtypes. The development of new TKIs and their integration into personalized treatment strategies will continue to shape the future of breast cancer therapy.

Lapatinib largely abrogated the anti-hypertrophic effect of FGF20, accompanied by increases in cardiomyocyte apoptosis and oxidative stress. In summary, this study reveals that FGF20 prevents cardiac hypertrophy by inhibiting apoptosis and oxidative stress via activating ErbB2 and may be a promising therapeutic strategy for cardiac hypertrophy.

A 54-year-old postmenopausal female patient with recurrent breast cancer and metastasis was treated with trastuzumab and paclitaxel (12 cycles), followed by trastuzumab maintenance therapy (71 cycles)...Oral therapy with lapatinib and letrozole was prescribed for a year to treat the breast cancer, along with the lesions and enhanced nodules observed in the patient's lungs, liver, and bones...This case report demonstrates the long-term efficacy of T-DM1 and its satisfactory safety profile. Overall, it provides valuable insights into the management of and challenges faced during the treatment of recurrent breast cancer with metastasis.

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. 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.

Amiloride combined with lapatinib significantly increased apoptosis but did not affect AR transcriptional activity. Thus, our data indicate that a combination of amiloride and lapatinib could target HSPC tumors without problems associated with androgen deprivation therapy in localized PCa.

The patients who progressed after trastuzumab-based chemotherapy and TDM-1 were included in the study...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.

Our findings demonstrated that lapatinib could effectively suppress the mRNA and protein expression of GPX4 in colon cancer cells, which elevates intracellular levels of ROS and malondialdehyde, ultimately inducing ferroptosis in these cells. This mechanism underscores the potential of lapatinib as a therapeutic strategy for targeting tumors.

Its enhancement of ALA-PDT was largely due to the increase of intracellular PpIX particularly in the mitochondria, resulting in the activation of mitochondria-mediated apoptosis in H4 cells. Our present study demonstrates that lapatinib inhibits ABCG2-mediated PpIX efflux and sensitizes GBM cells to ALA-PDT by inducing tumor cell death.

We established a NET-related five gene signature in SKCM and found that the NET-related signature may exhibit a good predictive ability for SKCM prognosis. The NET score may not only predict the survival outcome and drug sensitivity in SKCM, but also reflect the immune conditions of SKCM patients.

Additionally, compared to the low-risk group, the high-risk group exhibited significantly advanced tumor node metastasis (TNM) stages, lower proportions of activated CD4+ T cells, effector memory CD4+ T cells, and memory B cells, but increased ratios of M2 macrophages and regulatory T cells (Tregs), elevated tumor immune dysfunction and exclusion (TIDE) scores, and diminished sensitivity to dabrafenib, lapatinib, camptothecin, docetaxel, and telomerase inhibitor IX, reflecting the signature's capacity to distinguish clinical pathological characteristics, immune environment, and drug efficacy. Finally, we validated the expression of the ten TRDEGs (ACACB, TPX2, SRPX, PPARGC1A, CD36, MMP3, NAT2, MMP10, HIGD1A, and MMP1) through quantitative real-time polymerase chain reaction (qRT-PCR) and found that compared to normal cells, the expression levels of ACACB, HIGD1A, NAT2, PPARGC1A, and TPX2 in CRC cells were elevated, whereas those of CD36, SRPX, MMP1, MMP3, and MMP10 were reduced. Overall, we constructed a telomere-related biomarker capable of predicting prognosis and treatment response in CRC individuals, offering potential guidance for drug therapy selection and prognosis prediction.

Researchers have developed monoclonal antibodies like Trastuzumab and Pertuzumab against HER2 receptors, which have proven highly beneficial in cancer therapy. Bispecific antibodies like Zanidatamab and antibody-drug conjugates like T-DM1 have been developed to overcome the resistance associated with monotherapy. Small molecules such as Lapatinib, Neratinib, and Pyrotinib were initially developed for treating breast cancer...This comprehensive review covers the structural characteristics of HER2, the HER family signaling pathway mechanism, recent findings regarding HER2 receptor involvement in various cancers, and diverse HER2-targeted therapies. This information provides a comprehensive understanding of HER2-targeted strategies in the evolving field of cancer treatment.

Specifically, patients with the C1 subtype might respond to endocrine therapy or the p53-MDM2 antagonist nutlin-3...Patients with the C3 subtype might benefit from anti-HER2 agents such as lapatinib. Notably, to increase the clinical applicability of the EMT subtypes, we devised a 96-gene panel-based classifier via a machine learning framework. Our study identified three methylation-driven EMT subtypes with distinct prognoses and biological traits to capture heterogeneity in BC and provided a rationale for the use of this classification as a powerful tool for developing new strategies for clinical trials.

Compound 12k was found to be the most effective and rather selective dual-target inhibitor of EGFR and HER-2 with inhibitory constant (IC50) values of 6.15 and 9.78 nM, respectively, which was more potent than the clinical used agent Lapatinib (IC50 = 8.41 and 9.41 nM)...Notably, compound 12k could effectively inhibit breast cancer growth with little toxicity in the SK-BR-3 cell xenograft model. Taken together, in vitro and in vivo results disclosed that compound 12k had high drug potential as a dual-target inhibitor of EGFR/HER-2 to inhibit breast cancer growth.

P3, N=305, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Jul 2024 --> Jul 2025

In this article, we report the case of a patient with HER2+ metastatic breast cancer who developed brain metastases, despite experiencing a durable effect on extracranial metastases after treatment with trastuzumab and pertuzumab. The patient exhibited intracranial progression while receiving treatment with trastuzumab deruxtecan monotherapy after secondary brain radiotherapy and multiple lines of therapy with anti-HER2 agents, such as pyrotinib, lapatinib, tucatinib, and ado-trastuzumab emtansine...The present case indicates that the combination of anlotinib and trastuzumab deruxtecan may be a promising treatment option for patients with HER2+ breast cancer with brain metastasis. Nevertheless, further studies are warranted to verify the present findings.

Given the common hyperactivation of MAPK in IBC tumors, including rSUM149, we evaluated Merestinib, a multikinase inhibitor in clinical trials. It effectively targeted pERK and peIF4E pathways, suppressed downstream targets, induced cell death in drug-resistant rSUM149 cells, and showed synergistic effects with another tyrosine kinase inhibitor (Lapatinib) in parental cells. This underscores its significant impact on protein synthesis signaling, crucial for combating translational dependence in cancer cells. In summary, our study elucidates adaptive changes in IBC cells in response to therapy and treatment pauses, guiding precision medicine approaches for this challenging cancer type.

The results demonstrated that compound 6h displayed potent inhibitory activity, as concluded from the IC50 value (IC50 = 0.22 μM) compared to the standard drug Lapatinib (IC50 value of 0.18 μM). Compound 6h was found to induce significant cellular cycle arrest at the G1 phase and provoke apoptosis. Besides, compound 6h triggered apoptosis via upregulating p53 and initiator caspase 9 by 7.4- and 8.7-fold, respectively, compared to DMSO controls.

Currently, widely used clinical HER2 tyrosine kinase inhibitors (TKIs), such as lapatinib and neratinib, have several drawbacks, including susceptibility to drug resistance caused by HER2 mutations and adverse effects from insufficient HER2 selectivity...Typically, SPH5030 has advanced to phase I clinical trials for its strong suppression of four HER2 mutations. This review discusses the latest research progress in HER2 TKIs, with a focus on the structural optimization process and structure-activity relationship analysis. In particular, this study highlights promising design strategies to address these challenges, providing insightful information and inspiration for future development in this field.

A five-health state Markov model with lifetime horizon was used to assess the cost-utility of neoadjuvant trastuzumab (T) plus pertuzumab (P) or lapatinib (L) compared to single therapy of T with chemotherapy (C), in public healthcare system and societal perspectives. Even though only the ICER for strategy 3 was cost-effective, uncertainty of efficacy parameter was revealed. For strategy 2 neoadjuvant PTC plus adjuvant T, a 25% reduction of neoadjuvant regimen cost was required to be cost effective for use in early HER2 positive breast cancer.

Overexpression of ErbB2 in H9c2 cardiomyoblasts induced Notch1 activation in a post-transcriptional, p38-dependent manner, while ErbB2 inhibition with the specific inhibitor, lapatinib, reduced Notch1 activation...Furthermore, the hearts of transgenic mice specifically overexpressing ErbB2 in cardiomyocytes had increased levels of active Notch1 and of Notch-related genes. These data expand the knowledge of ErbB2 and Notch1 functions in the heart and may allow better understanding the mechanisms of the cardiotoxicity of ErbB2-targeting cancer treatments.

The safety and efficacy of pertuzumab and margetuximab in the treatment of gastric cancer have been verified...Small-molecule tyrosine kinase inhibitors, such as lapatinib and pyrrotinib, have the advantages of small molecular weight, penetrating the blood-brain barrier and high oral bioavailability, and are expected to become the drugs of choice for perioperative treatment and neoadjuvant therapy of gastric cancer after validation by large-scale clinical trials in the future. Antibo-drug conjugate, such as T-DM1 and T-DXd, can overcome the resistance of monoclonal antibodies despite their different mechanisms of tumor killing, and are a supplement for the treatment of patients who have failed the treatment of monoclonal antibodies such as trastuzumab. Therefore, after more detailed stratification of gastric cancer patients, various gastric cancer drugs targeting HER2 are expected to play a more significant role.

Moreover, patients with high-risk scores exhibited greater sensitivity to chemotherapy drugs such as lapatinib and had a lower immunotherapy response. Two TNBC clusters linked to disulfidptosis were identified, with different OS and immune cell infiltration. Moreover, a five-disulfidptosis-related gene signature may be a powerful prognostic biomarker for TNBC.

This study demonstrates an innovative TR EMPD-PDX model and introduces promising antineoplastic effects with various treatments for TR EMPD tumours.