Gastric cancer(GC) is a highly heterogenic disease,and it is the second leading cause of cancer death in the world.Common chemotherapies are not very effective for GC,which often presents as an advanced or metastatic ...Gastric cancer(GC) is a highly heterogenic disease,and it is the second leading cause of cancer death in the world.Common chemotherapies are not very effective for GC,which often presents as an advanced or metastatic disease at diagnosis.Treatment options are limited,and the prognosis for advanced GCs is poor.The landscape of genomic alterations in GCs has recently been characterized by several international cancer genome programs,including studies that focused exclusively on GCs in Asians.These studies identified major recurrent driver mutations and provided new insights into the mutational heterogeneity and genetic profiles of GCs.An analysis of gene expression data by the Asian Cancer Research Group(ACRG) further uncovered four distinct molecular subtypes with well-defined clinical features and their intersections with actionable genetic alterations to which targeted therapeutic agents are either already available or under clinical development.In this article,we review the ACRG GC project.We also discuss the implications of the genetic and molecular findings from various GC genomic studies with respect to developing more precise diagnoses and treatment approaches for GCs.展开更多
Targeted therapy has achieved significant success in the treatment of non-small cell lung cancer(NSCLC),particularly in patients harboring common oncogenic driver mutations such as EGFR,KRAS,and ALK rearrangement.Howe...Targeted therapy has achieved significant success in the treatment of non-small cell lung cancer(NSCLC),particularly in patients harboring common oncogenic driver mutations such as EGFR,KRAS,and ALK rearrangement.However,~35–50%of NSCLC patients without tyrosine kinase mutation or rearrangement(non-mutated)cannot benefit from these targeted treatments,highlighting the urgent need for novel therapeutic strategies for this patient population.In this study,we report a non-canonical role of human secretory ribonuclease 1(RNase1),which binds to and activates wild-type ALK in lung cancer cells,thereby triggering its downstream signaling pathway.RNase1-driven ALK-activation(RDAA)cells exhibit enhanced cell proliferation,migration,and colony formation.Additionally,RDAA facilitates tumor formation in fibroblast models,further underscoring its oncogenic potential in vivo.Importantly,RDAA lung cancer cells exhibit marked sensitivity to FDA-approved ALK inhibitors.Tumor growth suppression and survival were substantially improved in both RDAA-positive NSCLC cell line-derived and patient-derived xenograft tumor models treated with ALK inhibitors.Monoclonal antibodies against RNase1 and phosphorylated-ALK were used to analyze two different human NSCLC tissue cohorts by immunohistochemical staining identified 10.4%(5/48)and 8.5%(100/1173)patients who were RDAA positive,respectively.Notably,among the nine RDAA-positive NSCLC patients who accepted ALK inhibitor treatment,five achieved objective response including two who experienced complete response(CR).Together,the current study identifies RDAA as an oncogenic driver and proposes an effective targeted therapy strategy for non-mutated NSCLC patients.展开更多
文摘Gastric cancer(GC) is a highly heterogenic disease,and it is the second leading cause of cancer death in the world.Common chemotherapies are not very effective for GC,which often presents as an advanced or metastatic disease at diagnosis.Treatment options are limited,and the prognosis for advanced GCs is poor.The landscape of genomic alterations in GCs has recently been characterized by several international cancer genome programs,including studies that focused exclusively on GCs in Asians.These studies identified major recurrent driver mutations and provided new insights into the mutational heterogeneity and genetic profiles of GCs.An analysis of gene expression data by the Asian Cancer Research Group(ACRG) further uncovered four distinct molecular subtypes with well-defined clinical features and their intersections with actionable genetic alterations to which targeted therapeutic agents are either already available or under clinical development.In this article,we review the ACRG GC project.We also discuss the implications of the genetic and molecular findings from various GC genomic studies with respect to developing more precise diagnoses and treatment approaches for GCs.
基金The CAMS Innovation Fund for Medical Sciences(CIFMS,grant no.2021-I2M-C&T-A-021 to L.-X.L)the 1.3.5 Project for Disciplines of Excellence(Grants ZYJC21002 to L.-X.L.)+1 种基金National Institutes of Health Cancer Center Support Grant(P30CA016672 to M.-C.H.)The University of Texas MD Anderson-China Medical University and Hospital Sister Institution Fund(to M.-C.H.).
文摘Targeted therapy has achieved significant success in the treatment of non-small cell lung cancer(NSCLC),particularly in patients harboring common oncogenic driver mutations such as EGFR,KRAS,and ALK rearrangement.However,~35–50%of NSCLC patients without tyrosine kinase mutation or rearrangement(non-mutated)cannot benefit from these targeted treatments,highlighting the urgent need for novel therapeutic strategies for this patient population.In this study,we report a non-canonical role of human secretory ribonuclease 1(RNase1),which binds to and activates wild-type ALK in lung cancer cells,thereby triggering its downstream signaling pathway.RNase1-driven ALK-activation(RDAA)cells exhibit enhanced cell proliferation,migration,and colony formation.Additionally,RDAA facilitates tumor formation in fibroblast models,further underscoring its oncogenic potential in vivo.Importantly,RDAA lung cancer cells exhibit marked sensitivity to FDA-approved ALK inhibitors.Tumor growth suppression and survival were substantially improved in both RDAA-positive NSCLC cell line-derived and patient-derived xenograft tumor models treated with ALK inhibitors.Monoclonal antibodies against RNase1 and phosphorylated-ALK were used to analyze two different human NSCLC tissue cohorts by immunohistochemical staining identified 10.4%(5/48)and 8.5%(100/1173)patients who were RDAA positive,respectively.Notably,among the nine RDAA-positive NSCLC patients who accepted ALK inhibitor treatment,five achieved objective response including two who experienced complete response(CR).Together,the current study identifies RDAA as an oncogenic driver and proposes an effective targeted therapy strategy for non-mutated NSCLC patients.
