Objective： Although the kinase insert domain-containing receptor （KDR） gene play an very important role in the metastasis of cancer and is also as one of the molecular targets used in cancer therapy, mutation in th...Objective： Although the kinase insert domain-containing receptor （KDR） gene play an very important role in the metastasis of cancer and is also as one of the molecular targets used in cancer therapy, mutation in the tyrosine kinase （TK） domain of the KDR gene has not been reported. Here we detected the mutations and polymorphisms in the TK domain of KDR gene in human lung cancer patients and to give the basic evidence and clue for cancer prevention and target therapy. Methods： The entire sequence of exons 21, 22, 23 and 27 （which contain the coding sequence of tyrosine phosphorylation） in the TK domain of KDR gene in the patients with lung cancer and control healthy individuals were assayed by PCR and DNA sequencing. We also analyzed one non-coding single nucleotide polymorphisms （SNPs） in the KDR gene. Results： No mutations were found in exon 22, 23 and 27. One heterozygous mutation of c.＋2837 in exon 21 was found at a frequency of 2.08% （2/96） in the patients with lung cancer and none were detected in the healthy control individuals. The mutation was from a G to a A resulting in substitution of arginine with histidine residue. Conclusion： Our data suggested that we should focus on the mutation or SNP in the other regions or the expression levels of KDR gene, and the function of c.＋2837 mutation of KDR .qene may be needed further study in the future.展开更多
Uncommon epidermal growth factor receptor(EGFR) mutations account for 10% 20% of all EGFR mutations in non-small-cell lung cancer(NSCLC). The uncommon EGFR-mutated NSCLC is associated with poor clinical outcomes and g...Uncommon epidermal growth factor receptor(EGFR) mutations account for 10% 20% of all EGFR mutations in non-small-cell lung cancer(NSCLC). The uncommon EGFR-mutated NSCLC is associated with poor clinical outcomes and generally achieved unsatisfactory effects to the current therapies using standard EGFR-tyrosine kinase inhibitors(TKIs), including afatinib and osimertinib. Therefore, it is necessary to develop more novel EGFR-TKIs to treat uncommon EGFR-mutated NSCLC.Aumolertinib is a third-generation EGFR-TKI approved in China for treating advanced NSCLC with common EGFR mutations. However, it remains unclear whether aumolertinib is effective in uncommon EGFR-mutated NSCLC. In this work, the in vitro anticancer activity of aumolertinib was investigated in engineered Ba/F3 cells and patient-derived cells bearing diverse uncommon EGFR mutations. Aumolertinib was shown to be more potent in inhibiting the viability of various uncommon EGFR-mutated cell lines than those with wild-type EGFR. And in vivo, aumolertinib could also significantly inhibit tumor growth in two mouse allograft models(V769-D770insASV and L861Q mutations) and a patientderived xenografts model(H773-V774insNPH mutation). Importantly, aumolertinib exerts responses against tumors in advanced NSCLC patients with uncommon EGFR mutations. These results suggest that aumolertinib has the potential as a promising therapeutic candidate for the treatment of uncommon EGFR-mutated NSCLC.展开更多
基金Supported by the grants from the National Natural Science Foundation of China (No. 30772531)Guangdong Provincial Medical Science and Technology Research Foundation (No. B2006001)China Postdoctoral Science Foundation (No. 20060400212)
文摘Objective： Although the kinase insert domain-containing receptor （KDR） gene play an very important role in the metastasis of cancer and is also as one of the molecular targets used in cancer therapy, mutation in the tyrosine kinase （TK） domain of the KDR gene has not been reported. Here we detected the mutations and polymorphisms in the TK domain of KDR gene in human lung cancer patients and to give the basic evidence and clue for cancer prevention and target therapy. Methods： The entire sequence of exons 21, 22, 23 and 27 （which contain the coding sequence of tyrosine phosphorylation） in the TK domain of KDR gene in the patients with lung cancer and control healthy individuals were assayed by PCR and DNA sequencing. We also analyzed one non-coding single nucleotide polymorphisms （SNPs） in the KDR gene. Results： No mutations were found in exon 22, 23 and 27. One heterozygous mutation of c.＋2837 in exon 21 was found at a frequency of 2.08% （2/96） in the patients with lung cancer and none were detected in the healthy control individuals. The mutation was from a G to a A resulting in substitution of arginine with histidine residue. Conclusion： Our data suggested that we should focus on the mutation or SNP in the other regions or the expression levels of KDR gene, and the function of c.＋2837 mutation of KDR .qene may be needed further study in the future.
基金financial support from the National Natural Science Foundation of China (No. 82073402)the Key R&D Plan of Hubei Province (No. 2020BCA060)。
文摘Uncommon epidermal growth factor receptor(EGFR) mutations account for 10% 20% of all EGFR mutations in non-small-cell lung cancer(NSCLC). The uncommon EGFR-mutated NSCLC is associated with poor clinical outcomes and generally achieved unsatisfactory effects to the current therapies using standard EGFR-tyrosine kinase inhibitors(TKIs), including afatinib and osimertinib. Therefore, it is necessary to develop more novel EGFR-TKIs to treat uncommon EGFR-mutated NSCLC.Aumolertinib is a third-generation EGFR-TKI approved in China for treating advanced NSCLC with common EGFR mutations. However, it remains unclear whether aumolertinib is effective in uncommon EGFR-mutated NSCLC. In this work, the in vitro anticancer activity of aumolertinib was investigated in engineered Ba/F3 cells and patient-derived cells bearing diverse uncommon EGFR mutations. Aumolertinib was shown to be more potent in inhibiting the viability of various uncommon EGFR-mutated cell lines than those with wild-type EGFR. And in vivo, aumolertinib could also significantly inhibit tumor growth in two mouse allograft models(V769-D770insASV and L861Q mutations) and a patientderived xenografts model(H773-V774insNPH mutation). Importantly, aumolertinib exerts responses against tumors in advanced NSCLC patients with uncommon EGFR mutations. These results suggest that aumolertinib has the potential as a promising therapeutic candidate for the treatment of uncommon EGFR-mutated NSCLC.
