Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Preclinical and Basic Research Strategies for Overcoming Resistance to Targeted Therapies in HER2-Positive Breast Cancer.

ABSTRACT: The amplification of epidermal growth factor receptor 2 (HER2) is associated with a poor prognosis and HER2 gene is overexpressed in approximately 15-30% of breast cancers. In HER2-positive breast cancer patients, HER2-targeted therapies improved clinical outcomes and survival rates. However, drug resistance to anti-HER2 drugs is almost unavoidable, leaving some patients with an unmet need for better prognoses. Therefore, exploring strategies to delay or revert drug resistance is urgent. In recent years, new targets and regimens have emerged continuously. This review discusses the fundamental mechanisms of drug resistance in the targeted therapies of HER2-positive breast cancer and summarizes recent research progress in this field, including preclinical and basic research studies.

SUBMITTER: Cao Y

PROVIDER: S-EPMC10177527 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Preclinical and Basic Research Strategies for Overcoming Resistance to Targeted Therapies in HER2-Positive Breast Cancer.

Cao Yi Y Li Yunjin Y Liu Ruijie R Zhou Jianhua J Wang Kuansong K

Cancers 20230430 9

The amplification of epidermal growth factor receptor 2 (HER2) is associated with a poor prognosis and <i>HER2</i> gene is overexpressed in approximately 15-30% of breast cancers. In HER2-positive breast cancer patients, HER2-targeted therapies improved clinical outcomes and survival rates. However, drug resistance to anti-HER2 drugs is almost unavoidable, leaving some patients with an unmet need for better prognoses. Therefore, exploring strategies to delay or revert drug resistance is urgent. ...[more]

PMID: 37174034

Similar Datasets

Targeted Therapies Overcoming Endocrine Resistance in Hormone Receptor-Positive Breast Cancer.

Project description:Breast cancer is a heterogeneous disease with different molecular subtypes. Most tumours are hormone receptor positive (luminal subtype) with potential endocrine responsiveness. Endocrine therapy is commonly used in these patients. Disease progression caused by endocrine resistance represents a significant challenge in the treatment of breast cancer. To understand the mechanisms of resistance of long-term oestrogen-deprived breast cancer cells, it is important to focus on cross-talk between steroid receptor signalling and other growth factor receptors and intracellular pathways. (Pre-)clinical trials showed that co-targeting these pathways can restore endocrine sensitivity. The focus of the current review is on the intracellular PI3K/AKT/mTOR signalling pathway and cyclin-dependant kinases (CDKs) in oestrogen receptor (ER)-positive breast cancer. Study results clearly show that both inhibition of the PI3K/AKT/mTOR pathway and CDK4/6 are promising ways to improve the efficacy of endocrine treatment in ER-positive breast cancer patients with comparably few side effects. Further clinical trials are needed to identify the patient population who would benefit most from a dual inhibition.

| S-EPMC4569254 | biostudies-other

Overcoming resistance and restoring sensitivity to HER2-targeted therapies in breast cancer.

Project description:BackgroundApproximately 15%-23% of breast cancers overexpress human epidermal growth factor receptor 2 (HER2), which leads to the activation of signaling pathways that stimulate cell proliferation and survival. HER2-targeted therapy has substantially improved outcomes in patients with HER2-positive breast cancer. However, both de novo and acquired resistance are observed.DesignA literature search was performed to identify proposed mechanisms of resistance to HER2-targeted therapy and identified novel targets in clinical development for treating HER2-resistant disease.ResultsProposed HER2-resistance mechanisms include impediments to HER2-inhibitor binding, signaling through alternative pathways, upregulation of signaling pathways downstream of HER2, and failure to elicit an appropriate immune response. Although continuing HER2 inhibition beyond progression may provide an additional clinical benefit, the availability of novel therapies targeting different mechanisms of action could improve outcomes. The developmental strategy with the most available data is targeting the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (mTOR) pathway. The oral mTOR inhibitor everolimus has shown promising activity in combination with chemotherapy and trastuzumab in trastuzumab-refractory, advanced breast cancer.ConclusionsNon-HER2-targeted therapy is a promising means of overcoming resistance to HER2-targeted treatment. Ongoing clinical studies will provide additional information on the efficacy and safety of novel targeted therapies in HER2-resistant advanced breast cancer.

| S-EPMC3501233 | biostudies-literature

Novel Therapies and Strategies to Overcome Resistance to Anti-HER2-Targeted Drugs.

Project description:The prognosis and quality of life of HER2 breast cancer patients have significantly improved due to the crucial clinical benefit of various anti-HER2 targeted therapies. However, HER2 tumors can possess or develop several resistance mechanisms to these treatments, thus leaving patients with a limited set of additional therapeutic options. Fortunately, to overcome this problem, in recent years, multiple different and complementary approaches have been developed (such as antibody-drug conjugates (ADCs)) that are in clinical or preclinical stages. In this review, we focus on emerging strategies other than on ADCs that are either aimed at directly target the HER2 receptor (i.e., novel tyrosine kinase inhibitors) or subsequent intracellular signaling (e.g., PI3K/AKT/mTOR, CDK4/6 inhibitors, etc.), as well as on innovative approaches designed to attack other potential tumor weaknesses (such as immunotherapy, autophagy blockade, or targeting of other genes within the HER2 amplicon). Moreover, relevant technical advances such as anti-HER2 nanotherapies and immunotoxins are also discussed. In brief, this review summarizes the impact of novel therapeutic approaches on current and future clinical management of aggressive HER2 breast tumors.

| S-EPMC9496705 | biostudies-literature

Overcoming Resistance to HER2-Directed Therapies in Breast Cancer.

Project description:Human epidermal growth factor receptor 2 (HER2)-positive breast cancer accounts for around 15% of all breast cancers and was historically associated with a worse prognosis compared with other breast cancer subtypes. With the development of HER2-directed therapies, the outcomes of patients with HER2-positive disease have improved dramatically; however, many patients present with de novo or acquired resistance to these therapies, which leads to early recurrences or progression of advanced disease. In this narrative review, we discuss the mechanisms of resistance to different HER2-targeted therapies, including monoclonal antibodies, small tyrosine kinase inhibitors, and antibody-drug conjugates. We review mechanisms such as impaired binding to HER2, incomplete receptor inhibition, increased signaling from other receptors, cross-talk with estrogen receptors, and PIK3CA pathway activation. We also discuss the role of the tumor immune microenvironment and HER2-heterogeneity, and the unique mechanisms of resistance to novel antibody-drug conjugates. A better understanding of these mechanisms and the potential strategies to overcome them will allow us to continue improving outcomes for patients with breast cancer.

| S-EPMC9406173 | biostudies-literature

Emerging Targeted Therapies for HER2 Positive Gastric Cancer That Can Overcome Trastuzumab Resistance.

Project description:Trastuzumab, a monoclonal antibody to human epidermal growth factor receptor 2 (HER2), has improved survival in patients with HER2-positive advanced gastric or gastroesophageal junction cancer (AGC). The inevitable development of resistance to trastuzumab remains a problem, however, with several treatment strategies that have proven effective in breast cancer having failed to show clinical benefit in AGC. In this review, we summarize the mechanisms underlying resistance to HER2-targeted therapy and outline past and current challenges in the treatment of HER2-positive AGC refractory to trastuzumab. We further describe novel agents such as HER2 antibody-drug conjugates that are under development and have shown promising antitumor activity in early studies.

| S-EPMC7072407 | biostudies-literature

Emerging Targeted Therapies for HER2-Positive Breast Cancer.

Project description:Breast cancer is the most common cancer in women and the leading cause of death. HER2 overexpression is found in approximately 20% of breast cancers and is associated with a poor prognosis and a shorter overall survival. Tratuzumab, a monoclonal antibody directed against the HER2 receptor, is the standard of care treatment. However, a third of the patients do not respond to therapy. Given the high rate of resistance, other HER2-targeted strategies have been developed, including monoclonal antibodies such as pertuzumab and margetuximab, trastuzumab-based antibody drug conjugates such as trastuzumab-emtansine (T-DM1) and trastuzumab-deruxtecan (T-DXd), and tyrosine kinase inhibitors like lapatinib and tucatinib, among others. Moreover, T-DXd has proven to be of use in the HER2-low subtype, which suggests that other HER2-targeted therapies could be successful in this recently defined new breast cancer subclassification. When patients progress to multiple strategies, there are several HER2-targeted therapies available; however, treatment options are limited, and the potential combination with other drugs, immune checkpoint inhibitors, CAR-T cells, CAR-NK, CAR-M, and vaccines is an interesting and appealing field that is still in development. In this review, we will discuss the highlights and pitfalls of the different HER2-targeted therapies and potential combinations to overcome metastatic disease and resistance to therapy.

| S-EPMC10093019 | biostudies-literature

Drug-resistant HER2-positive breast cancer: Molecular mechanisms and overcoming strategies

Project description:Breast cancer is one of the most common malignancies and the leading cause of cancer-related death in women. HER2 overexpression is a factor for poor prognosis in breast cancer, and anti-HER2 therapy improves survival in these patients. A dual-targeted combination of pertuzumab and trastuzumab, alongside cytotoxic chemotherapy, constitutes the primary treatment option for individuals with early-stage, HER2-positive breast cancer. Antibody-drug conjugate (ADC) and tyrosine kinase inhibitors (TKI) also increase the prognosis for patients with metastatic breast cancer. However, resistance to targeted therapy eventually occurs. Therefore, it is critical to investigate how HER2-positive breast cancer is resistant to targeted therapy and to develop novel drugs or strategies to overcome the resistance simultaneously. This review aims to provide a comprehensive discussion of the HER2-targeted agents currently in clinical practice, the molecular mechanisms of resistance to these drugs, and the potential strategies for overcoming resistance.

| S-EPMC9540370 | biostudies-literature

Overcoming resistance to targeted therapies in chronic lymphocytic leukemia.

Project description:Insight into the critical role of B-cell receptor signaling for the pathogenesis of chronic lymphocytic leukemia (CLL) led to the development of targeted therapies directed at key regulators of cell survival. Agents targeting B-cell lymphoma-2 protein, Bruton's tyrosine kinase (BTK), and phosphatidylinositol 3-kinase are approved for treatment of CLL, and have significantly improved the disease management. Nevertheless, acquired resistance to the targeted therapies is a challenge still to be resolved. The mechanisms underlying resistance are becoming clearer, and include secondary mutations within the drug target and activation of bypass pathways. This knowledge has allowed development of strategies to prevent and overcome treatment resistance. Approaches to prevent resistance include targeting bypass mechanisms by combination therapies, temporally sequencing of therapies, improved clinical trial designs, and real-time monitoring of patient response. A rational design of drug sequencing may secure effective treatment options at the relapsed setting. Next-generation inhibitors and bispecific antibodies have the potential to overcome resistance to the BTK inhibitor ibrutinib. Immunotherapy, including chimeric antigen receptor-modified T-cell therapy, is explored for relapsed CLL. Here, recent advances that have contributed to the understanding of resistance to targeted therapies in CLL are discussed. Strategies for managing resistance are reviewed, including translational, real-world, and clinical perspectives.

| S-EPMC7805313 | biostudies-literature

Overcoming resistance to HER2-targeted therapy with a novel HER2/CD3 bispecific antibody.

Project description:T-cell-based therapies have emerged as one of the most clinically effective ways to target solid and non-solid tumors. HER2 is responsible for the oncogenesis and treatment resistance of several human solid tumors. As a member of the HER family of tyrosine kinase receptors, its over-activity confers unfavorable clinical outcome. Targeted therapies directed at this receptor have achieved responses, although development of resistance is common. We explored a novel HER2/CD3 bispecific antibody (HER2-BsAb) platform that while preserving the anti-proliferative effects of trastuzumab, it recruits and activates non-specific circulating T-cells, promoting T cell tumor infiltration and ablating HER2(+) tumors, even when these are resistant to standard HER2-targeted therapies. Its in vitro tumor cytotoxicity, when expressed as EC50, correlated with the surface HER2 expression in a large panel of human tumor cell lines, irrespective of lineage or tumor type. HER2-BsAb-mediated cytotoxicity was relatively insensitive to PD-1/PD-L1 immune checkpoint inhibition. In four separate humanized mouse models of human breast cancer and ovarian cancer cell line xenografts, as well as human breast cancer and gastric cancer patient-derived xenografts (PDXs), HER2-BsAb was highly effective in promoting T cell infiltration and suppressing tumor growth when used in the presence of human peripheral blood mononuclear cells (PBMC) or activated T cells (ATC). The in vivo and in vitro antitumor properties of this BsAb support its further clinical development as a cancer immunotherapeutic.

| S-EPMC5384386 | biostudies-literature

HER2-positive breast cancer: new therapeutic frontiers and overcoming resistance.

Project description:The introduction of anti-HER2 therapies to the treatment of patients with HER2-positive breast cancer has led to dramatic improvements in survival in both early and advanced settings. Despite this breakthrough, nearly all patients with metastatic HER2-positive breast cancer eventually progress on anti-HER2 therapy due to de novo or acquired resistance. A better understanding not only of the underlying mechanisms of HER2 therapy resistance but of tumor heterogeneity as well as the host and tumor microenvironment is essential for the development of new strategies to further improve patient outcomes. One strategy has focused on inhibiting the HER2 signaling pathway more effectively with dual-blockade approaches and developing improved anti-HER2 therapies like antibody-drug conjugates, new anti-HER2 antibodies, bispecific antibodies, or novel tyrosine kinase inhibitors that might replace or be used in addition to some of the current anti-HER2 treatments. Combinations of anti-HER2 therapy with other agents like immune checkpoint inhibitors, CDK4/6 inhibitors, and PI3K/AKT/mTOR inhibitors are also being extensively evaluated in clinical trials. These add-on strategies of combining optimized targeted therapies could potentially improve outcomes for patients with HER2-positive breast cancer but may also allow de-escalation of treatment in some patients, potentially sparing some from unnecessary treatments, and their related toxicities and costs.

| S-EPMC6425535 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data