Targeted lapatinib anti-HER2/ErbB2 therapy resistance in breast cancer:opportunities to overcome a difficult problem  

作　　者：Reema Wahdan-Alaswad Bolin Liu Ann D.Thor 

机构地区：[1]Department of Pathology,University of Colorado Anschutz Medical Campus,Aurora CO 80014,USA [2]Department of Genetics,Stanley S.Scott Cancer Center,School of Medicine,Louisiana State University Health Sciences Center,New Orleans,LA 70112,USA

出　　处：《Cancer Drug Resistance》2020年第2期179-198,共20页癌症耐药（英文）

基　　金：Grant support provided in part by Susan G Komen for the Cure K100575 to RSW,SME,and ADT;ACS-IRG 16-184-56 RSW from the American Cancer Society;CCL-C92110 RSW and ADT from the Colorado Cancer League.

摘　　要：Approximately 20%of invasive breast cancers have upregulation/gene amplification of the oncogene human epidermal growth factor receptor-2(HER2/ErbB2).Of these,some also express steroid receptors(the so-called Luminal B subtype),whereas others do not(the HER2 subtype).HER2 abnormal breast cancers are associated with a worse prognosis,chemotherapy resistance,and sensitivity to selected anti-HER2 targeted therapeutics.Transcriptional data from over 3000 invasive breast cancers suggest that this approach is overly simplistic;rather,the upregulation of HER2 expression resulting from gene amplification is a driver event that causes major transcriptional changes involving numerous genes and pathways in breast cancer cells.Most notably,this includes a shift from estrogenic dependence to regulatory controls driven by other nuclear receptors,particularly the androgen receptor.We discuss members of the HER receptor tyrosine kinase family,heterodimer formation,and downstream signaling,with a focus on HER2 associated pathology in breast carcinogenesis.The development and application of anti-HER2 drugs,including selected clinical trials,are discussed.In light of the many excellent reviews in the clinical literature,our emphasis is on recently developed and successful strategies to overcome targeted therapy resistance.These include combining anti-HER2 agents with programmed cell death-1 ligand or cyclin-dependent kinase 4/6 inhibitors,targeting crosstalk between HER2 and other nuclear receptors,lipid/cholesterol synthesis to inhibit receptor tyrosine kinase activation,and metformin,a broadly inhibitory drug.We seek to facilitate a better understanding of new approaches to overcome anti-HER2 drug resistance and encourage exploration of two other therapeutic interventions that may be clinically useful for HER+invasive breast cancer patients.

关 键 词：HER2/ErbB2 receptor tyrosine kinase tyrosine kinase resistance nuclear receptor androgen receptor lipid metabolism programmed cell death-1 ligand CDK 4/6 inhibitor 

分 类 号：R73[医药卫生—肿瘤]