Drugs that specifically target the tyrosine kinase domain of epidermal growth factor receptor(EGFR), such as erlotinib or gefitinib, have exhibited striking efficacy in non-small cell lung cancer(NSCLC) patients harbo...Drugs that specifically target the tyrosine kinase domain of epidermal growth factor receptor(EGFR), such as erlotinib or gefitinib, have exhibited striking efficacy in non-small cell lung cancer(NSCLC) patients harboring activating EGFR mutations. However, acquired resistance inevitably develops and remains a serious barrier for the successful management of patients with this disease. Multiple mechanisms are reportedly involved in the process of acquired resistance, which provide new insights into the management of EGFRtyrosine kinase inhibitor(EGFR-TKI) resistance. Here, we provide an overview of the emerging treatment approaches for patients with EGFR-TKI resistance.展开更多
Hyperactive RAS/RAF/MEK/ERK signaling has a well-defined role in cancer biology.Targeting this pathway results in complete or partial regression of most cancers.In recent years,cancer genomic studies have revealed tha...Hyperactive RAS/RAF/MEK/ERK signaling has a well-defined role in cancer biology.Targeting this pathway results in complete or partial regression of most cancers.In recent years,cancer genomic studies have revealed that genetic alterations that aberrantly activate the RAS/RAF/MEK/ERK signaling mainly occur on RAF or upstream,which motivated the extensive development of RAF inhibitors for cancer therapy.Currently,the first-generation RAF inhibitors have been approved for treating late-stage cancers with BRAF(V600E)mutations.Although these inhibitors have achieved promising outcomes in clinical treatments,their efficacy is abolished by quick-rising drug resistance.Moreover,cancers with hyperactive RAS exhibit intrinsic resistance to these drugs.To resolve these problems,the second-generation RAF inhibitors have been designed and are undergoing clinical evaluations.Here,we summarize the recent findings from mechanistic studies on RAF inhibitor resistance and discuss the critical issues in the development of next-generation RAF inhibitors with better therapeutic index,which may provide insights for improving targeted cancer therapy with RAF inhibitors.展开更多
Despite the promising initial anti-tumor efficacy of epidermal growth factor receptor-tyrosine kinase inhibitors(EGFR-TKIs),most advanced non-small-cell lung cancers(NSCLCs)progress eventually due to therapeutic resis...Despite the promising initial anti-tumor efficacy of epidermal growth factor receptor-tyrosine kinase inhibitors(EGFR-TKIs),most advanced non-small-cell lung cancers(NSCLCs)progress eventually due to therapeutic resistance.V-Raf murine sarcoma viral oncogene homolog B1(BRAF)^(V600E) mutation has been considered as an uncommon mutation that contributes to acquired resistance for EGFR-TKIs.In the presented case,BRAF^(V600E) mutation was detected as an acquired resistance-mediated mutation in a patient treated with osimertinib(a third-generation EGFR-TKI).The presented patient achieved partial regression and ongoing PFS of four months after the co-inhibition of osimertinib plus dabrafenib(BRAF inhibitor)and trametinib(MEK inhibitor).Our case further enriches the clinical evidence of the efficacy of EGFR/BRAF/MEK co-inhibition in patients with an acquired BRAF^(V600E) mutation,consistent with the review of the literature(eight cases).Additionally,our case highlights the important role of sample type,method,and platform of gene detection in patient management,life quality,and prognosis,as well as the understanding of acquired resistance mechanism.展开更多
文摘Drugs that specifically target the tyrosine kinase domain of epidermal growth factor receptor(EGFR), such as erlotinib or gefitinib, have exhibited striking efficacy in non-small cell lung cancer(NSCLC) patients harboring activating EGFR mutations. However, acquired resistance inevitably develops and remains a serious barrier for the successful management of patients with this disease. Multiple mechanisms are reportedly involved in the process of acquired resistance, which provide new insights into the management of EGFRtyrosine kinase inhibitor(EGFR-TKI) resistance. Here, we provide an overview of the emerging treatment approaches for patients with EGFR-TKI resistance.
基金This study was funded by Asia Fund for Cancer Research(AFCR-2017/2019-JH)SingHealth Foundation(AM/TP011/2018)+1 种基金National Medical Research Council(OFIRG18nov-0078)Duke-NUS Medical School Khoo Foundation(Duke-NUS-KBrFA/2020/0036)to Jiancheng Hu.
文摘Hyperactive RAS/RAF/MEK/ERK signaling has a well-defined role in cancer biology.Targeting this pathway results in complete or partial regression of most cancers.In recent years,cancer genomic studies have revealed that genetic alterations that aberrantly activate the RAS/RAF/MEK/ERK signaling mainly occur on RAF or upstream,which motivated the extensive development of RAF inhibitors for cancer therapy.Currently,the first-generation RAF inhibitors have been approved for treating late-stage cancers with BRAF(V600E)mutations.Although these inhibitors have achieved promising outcomes in clinical treatments,their efficacy is abolished by quick-rising drug resistance.Moreover,cancers with hyperactive RAS exhibit intrinsic resistance to these drugs.To resolve these problems,the second-generation RAF inhibitors have been designed and are undergoing clinical evaluations.Here,we summarize the recent findings from mechanistic studies on RAF inhibitor resistance and discuss the critical issues in the development of next-generation RAF inhibitors with better therapeutic index,which may provide insights for improving targeted cancer therapy with RAF inhibitors.
基金This work was supported by the Shanghai Municipal Key Clinical Specialty(shslczdzk02202)the National Natural Science Foundation of China(81672271).
文摘Despite the promising initial anti-tumor efficacy of epidermal growth factor receptor-tyrosine kinase inhibitors(EGFR-TKIs),most advanced non-small-cell lung cancers(NSCLCs)progress eventually due to therapeutic resistance.V-Raf murine sarcoma viral oncogene homolog B1(BRAF)^(V600E) mutation has been considered as an uncommon mutation that contributes to acquired resistance for EGFR-TKIs.In the presented case,BRAF^(V600E) mutation was detected as an acquired resistance-mediated mutation in a patient treated with osimertinib(a third-generation EGFR-TKI).The presented patient achieved partial regression and ongoing PFS of four months after the co-inhibition of osimertinib plus dabrafenib(BRAF inhibitor)and trametinib(MEK inhibitor).Our case further enriches the clinical evidence of the efficacy of EGFR/BRAF/MEK co-inhibition in patients with an acquired BRAF^(V600E) mutation,consistent with the review of the literature(eight cases).Additionally,our case highlights the important role of sample type,method,and platform of gene detection in patient management,life quality,and prognosis,as well as the understanding of acquired resistance mechanism.
