Triple-negative breast cancer(TNBC)is the most aggressive breast cancer subtype.It disproportionately affects BRCA mutation carriers and young women,especially African American(AA)women.Chemoresistant TNBC is a hetero...Triple-negative breast cancer(TNBC)is the most aggressive breast cancer subtype.It disproportionately affects BRCA mutation carriers and young women,especially African American(AA)women.Chemoresistant TNBC is a heterogeneous and molecularly unstable disease that challenges our ability to apply personalized therapies.With 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 TNBC.Pembrolizumab plus chemotherapy significantly increased the pathologic complete response(pCR)and improved event-free survival in TNBC.However,clinical uncertainties remain because similarly treated TNBC partial responders with comparable tumor responses to neoadjuvant therapy often experience disparate clinical outcomes.Current methods fall short in accurately predicting which high-risk patients will develop chemo-resistance and tumor relapse.Therefore,novel treatment strategies and innovative new research initiatives are needed.We propose that the EGFR-K-RAS-SIAH pathway activation is a major tumor driver in chemoresistant TNBC.Persistent 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 treatment.These chemoresistant tumor clones persist in expressing SIAH(SIAH^(High/ON))and are linked to early tumor relapse and poorer prognosis.Conversely,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 cells.SIAH^(Low/OFF) signal is linked to tumor remission and better prognosis post-NACT/NST.Therefore,SIAH is well-positioned to become a novel tumor-specific,therapy-responsive,and prognostic biomarker.Potentially,this new biomarker(SIAH^(High/ON))could be used to quantify therapy response,predict chemo-resistance,and identify those patients at the highest risk for tumor relapse and poor survival in TNBC.展开更多
肺癌是目前发病率和病死率最高的恶性肿瘤,其中约80%为非小细胞肺癌（non small cell lung cancer,NSCLC）。目前,肺癌可以简单分为：EGFR突变型、K-RAS突变型、ALK融合型及其他型。对于前3种肺癌亚型目前均有相应的靶向药物治疗。第四...肺癌是目前发病率和病死率最高的恶性肿瘤,其中约80%为非小细胞肺癌（non small cell lung cancer,NSCLC）。目前,肺癌可以简单分为：EGFR突变型、K-RAS突变型、ALK融合型及其他型。对于前3种肺癌亚型目前均有相应的靶向药物治疗。第四型约占肺癌的25%,展开更多
基金supported by DOD-BCRP Level II Breakthrough Award(BC180907 to A.H.T.)National Institutes of Health National Cancer Institute(R01 CA140550 to A.H.T.)+1 种基金the Center for Innovative Technology(CIT)-Commonwealth Research Commercialization Fund(CRCF)(MF14S-009-LS to A.H.T.)Dorothy G.Hoefer Foundation(Breast Cancer Grant to A.H.T.).
文摘Triple-negative breast cancer(TNBC)is the most aggressive breast cancer subtype.It disproportionately affects BRCA mutation carriers and young women,especially African American(AA)women.Chemoresistant TNBC is a heterogeneous and molecularly unstable disease that challenges our ability to apply personalized therapies.With 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 TNBC.Pembrolizumab plus chemotherapy significantly increased the pathologic complete response(pCR)and improved event-free survival in TNBC.However,clinical uncertainties remain because similarly treated TNBC partial responders with comparable tumor responses to neoadjuvant therapy often experience disparate clinical outcomes.Current methods fall short in accurately predicting which high-risk patients will develop chemo-resistance and tumor relapse.Therefore,novel treatment strategies and innovative new research initiatives are needed.We propose that the EGFR-K-RAS-SIAH pathway activation is a major tumor driver in chemoresistant TNBC.Persistent 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 treatment.These chemoresistant tumor clones persist in expressing SIAH(SIAH^(High/ON))and are linked to early tumor relapse and poorer prognosis.Conversely,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 cells.SIAH^(Low/OFF) signal is linked to tumor remission and better prognosis post-NACT/NST.Therefore,SIAH is well-positioned to become a novel tumor-specific,therapy-responsive,and prognostic biomarker.Potentially,this new biomarker(SIAH^(High/ON))could be used to quantify therapy response,predict chemo-resistance,and identify those patients at the highest risk for tumor relapse and poor survival in TNBC.
基金support from the National Natural Science Foundation of China(No.81774126,No.81503445 and No.81703919)China Postdoctoral Science Foundation(No.2017M622587)+5 种基金Hunan Provincial Natural Science Foundation(No.2016JJ2095 and No.2017JJ3232)Hunan Provincial Traditional Chinese Medicine Key Research Project(No.201701)Hunan Education Department Scientific Research Project(16C1203 and 16C1216)Hunan Health Department Scientific Research Project(C2015-16,C2016049 and B2016093)Busky Pharmaceutical Collaborative Research Fund,Hunan Provincial Higher Educational Institutions Research Team "Traditional Chinese Medicine prevention and treatment research on infectious diseases" Funding program(No.15)Hunan Province Teaching and Science "Thirteenth Five-Year Plan" Project(No.XJK17BGD057)
