Thioridazine reverses trastuzumab resistance in gastric cancer by inhibiting S-phase kinase associated protein 2-mediated aerobic glycolysis

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.

Long non-coding RNA-ATB induces trastuzumab resistance and aggravates the progression of gastric cancer by repressing miR- 200c via ZNF217 elevation

Background: Trastuzumab resistance accounts for chemotherapy failure in gastric cancer patients in clinicalpractice. The significance of long non-coding RNAs (lncRNAs) in the maintenance of drug resistance in gastriccancer has been already underlined. Method: This study aimed to identify the specific role of lncRNA-ATB in gastriccancer progression and trastuzumab resistance. The downstream miRs of lncRNA-ATB and target genes of miRs werepredicted by bioinformatics analysis and verified using dual luciferase reporter assay. Loss- and gain-function assayswere performed to explore the roles of lncRNA-ATB, miR-200c, and zinc-finger protein 217 (ZNF217) in the cellfunctions and trastuzumab resistance of a trastuzumab-resistant gastric cancer cell line (NCI-N87-TR). Result:LncRNA-ATB was upregulated, while miR-200c was downregulated. Depletion of lncRNA-ATB or miR-200celevation led to a decrease in malignant properties of NCI-N87-TR cells. LncRNA-ATB could negatively target miR-200c, which in turn inversely targeted and reduced the expression of ZNF217. Silencing of ZNF217 could inhibit cellviability and migration. Conclusion: lncRNA-ATB promoted the progression and trastuzumab resistance of gastriccancer by repressing miR-200c via ZNF217 upregulation.

Nanoparticles(NPs)-mediated systemic mRNA delivery to reverse trastuzumab resistance for effective breast cancer therapy

Monoclonal antibody-based therapy has achieved great success and is now one of the most crucial therapeutic modalities for cancer therapy.The first monoclonal antibody authorized for treating human epidermal growth receptor 2(HER2)-positive breast cancer is trastuzumab.However,resistance to trastuzumab therapy is frequently encountered and thus significantly restricts the therapeutic outcomes.To address this issue,tumor microenvironment(TME)pH-responsive nanoparticles(NPs)were herein developed for systemic mRNA delivery to reverse the trastuzumab resistance of breast cancer(BCa).This nanoplatform is comprised of a methoxyl-poly(ethylene glycol)-b-poly(lactic-co-glycolic acid)copolymer with a TME pH-liable linker(Meo-PEG-Dlinkm-PLGA)and an amphiphilic cationic lipid that can complex PTEN mRNA via electrostatic interaction.When the long-circulating mRNA-loaded NPs build up in the tumor after being delivered intravenously,they could be efficiently internalized by tumor cells due to the TME pH-triggered PEG detachment from the NP surface.With the intracellular mRNA release to up-regulate PTEN expression,the constantly activated PI3K/Akt signaling pathway could be blocked in the trastuzumab-resistant BCa cells,thereby resulting in the reversal of trastuzumab resistance and effectively suppress the development of BCa.

Inetetamab combined with pyrotinib and chemotherapy in the treatment of breast cancer brain metastasis: A case report

BACKGROUND Breast cancer brain metastasis(BCBM)is an advanced breast disease that is difficult to treat and is associated with a high risk of death.Patient prognosis is usually poor,with reduced quality of life.In this context,we report the case of a patient with HER-2-positive BCBM treated with a macromolecular mAb(ine-tetamab)combined with a small molecule tyrosine kinase inhibitor(TKI).CASE SUMMARY The patient was a 58-year-old woman with a 12-year history of type 2 diabetes.She was compliant with regular insulin treatment and had good blood glucose control.The patient was diagnosed with invasive carcinoma of the right breast(T3N1M0 stage IIIa,HER2-positive type)through aspiration biopsy of the ipsilateral breast due to the discovery of a breast tumor in February 2019.Immunohistochemistry showed ER(-),PR(-),HER-2(3+),and Ki-67(55-60%+).Preoperative neoadjuvant chemotherapy,i.e.,the AC-TH regimen(epirubicin,cyclophosphamide,docetaxel-paclitaxel,and trastuzumab),was administered for 8 cycles.She underwent modified radical mastectomy of the right breast in November 2019 and received tocilizumab targeted therapy for 1 year.Brain metastasis was found 9 mo after surgery.She underwent brain metastasectomy in August 2020.Immunohistochemistry showed ER(-)and PR.(-),HER-2(3+),and Ki-67(10-20%+).In November 2020,the patient experienced headache symptoms.After an examination,tumor recurrence in the original surgical region of the brain was observed,and the patient was treated with inetetamab,pyrotinib,and capecitabine.Whole-brain radiotherapy was recommended.The patient and her family refused radiotherapy for personal reasons.In September 2021,a routine examination revealed that the brain tumor was considerably larger.The original systemic treatment was continued and combined with intensity-modulated radiation therapy for brain metastases,followed by regular hospitalization and routine examinations.The patient’s condition is generally stable,and she has a relatively high quality of life.This case report demonstrates that in patients with BCBM and resistance to trastuzumab,inetetamab combined with pyrotinib and chemotherapy can prolong survival.CONCLUSION Inetetamab combined with small molecule TKI drugs,chemotherapy and radiation may be an effective regimen for maintaining stable disease in patients with BCBM.