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Persistent EGFR/K-RAS/SIAH pathway activation drives chemo-resistance and early tumor relapse in triple-negative breast cancer

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Cancer Drug Resistance 2022年第3期5卷 691-702页

作者： Amy H.Tang Richard A.Hoefer Mary L.Guye Harry D.Bear Department of Microbiology and Molecular Cell Biology Leroy T.Canoles Jr.Cancer Research CenterEastern Virginia Medical SchoolNorfolkVA 23507USA School of Systems Biology George Mason UniversityManassasVA 20110USA Sentara Cancer Network Sentara HealthcareNorfolkVA 23507USA Sentara Surgery Specialists Surgical OncologySentara CarePlex HospitalNewport NewsVA 23606USA Division of Surgical Oncology Departments of Surgery and Microbiology and ImmunologyMassey Cancer CenterVirginia Commonwealth UniversityRichmondVA 23298-0011USA

Triple-negative breast cancer(TNBC)is the most aggressive breast cancer *** disproportionately affects BRCA mutation carriers and young women,especially African American(AA)*** TNBC is a heterogeneous and molecularly unstable disease that challenges our ability to apply personalized *** the approval of immune checkpoint blockade(ICB)for TNBC,the addition of pembrolizumab to systemic chemotherapy has become standard of care(SOC)in neoadjuvant systemic therapy(NST)for high-risk early-stage *** plus chemotherapy significantly increased the pathologic complete response(pCR)and improved event-free survival in ***,clinical uncertainties remain because similarly treated TNBC partial responders with comparable tumor responses to neoadjuvant therapy often experience disparate clinical *** methods fall short in accurately predicting which high-risk patients will develop chemo-resistance and tumor ***,novel treatment strategies and innovative new research initiatives are *** propose that the EGFR-K-RAS-SIAH pathway activation is a major tumor driver in chemoresistant *** high expression of SIAH in residual tumors following NACT/NST reflects that the EGFR/K-RAS pathway remains activated(ON),indicating an ineffective response to *** chemoresistant tumor clones persist in expressing SIAH(SIAH^(High/ON))and are linked to early tumor relapse and poorer ***,the loss of SIAH expression(SIAH^(Low/OFF))in residual tumors post-NACT/NST reflects EGFR/K-RAS pathway inactivation(OFF),indicating effective therapy and chemo-sensitive tumor ***^(Low/OFF) signal is linked to tumor remission and better prognosis post-NACT/***,SIAH is well-positioned to become a novel tumor-specific,therapy-responsive,and prognostic ***,this new biomarker(SIAH^(High/ON))could be used to quantify therapy response,predict chemo-resistance,and identi

关键词： Triple-negative breast cancer(TNBC) chemo-resistance seven in absentia(SINA)and human homologs of SINA(SIAH)E3 ligase ubiquitin-mediated proteolysis EGFR/K-RAS/SIAH pathway activation in TNBC neoadjuvant chemotherapy prognosis patient risk stratification detection of chemo-resistance precision quantification of therapy efficacy and treatment optimization

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