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EGF Induced RET Inhibitor Resistance in <i>CCDC6-RET</i> Lung Cancer Cells
Chang, Hyun,Sung, Ji Hea,Moon, Sung Ung,Kim, Han-Soo,Kim, Jin Won,Lee, Jong Seok Yonsei University, College of Medicine 2017 Yonsei medical journal Vol.58 No.1
<P><B>Purpose</B></P><P>Rearrangement of the proto-oncogene <I>rearranged during transfection</I> (<I>RET</I>) has been newly identified potential driver mutation in lung adenocarcinoma. Clinically available tyrosine kinase inhibitors (TKIs) target RET kinase activity, which suggests that patients with <I>RET</I> fusion genes may be treatable with a kinase inhibitor. Nevertheless, the mechanisms of resistance to these agents remain largely unknown. Thus, the present study aimed to determine whether epidermal growth factor (EGF) and hepatocyte growth factor (HGF) trigger RET inhibitor resistance in LC-2/ad cells with <I>CCDC6-RET</I> fusion genes.</P><P><B>Materials and Methods</B></P><P>The effects of EGF and HGF on the susceptibility of a <I>CCDC6-RET</I> lung cancer cell line to RET inhibitors (sunitinib, E7080, vandetanib, and sorafenib) were examined.</P><P><B>Results</B></P><P><I>CCDC6-RET</I> lung cancer cells were highly sensitive to RET inhibitors. EGF activated epidermal growth factor receptor (EGFR) and triggered resistance to sunitinib, E7080, vandetanib, and sorafenib by transducing bypass survival signaling through ERK and AKT. Reversible EGFR-TKI (gefitinib) resensitized cancer cells to RET inhibitors, even in the presence of EGF. Endothelial cells, which are known to produce EGF, decreased the sensitivity of <I>CCDC6-RET</I> lung cancer cells to RET inhibitors, an effect that was inhibited by EGFR small interfering RNA (siRNA), anti-EGFR antibody (cetuximab), and EGFR-TKI (Iressa). HGF had relatively little effect on the sensitivity to RET inhibitors.</P><P><B>Conclusion</B></P><P>EGF could trigger resistance to RET inhibition in <I>CCDC6-RET</I> lung cancer cells, and endothelial cells may confer resistance to RET inhibitors by EGF. E7080 and other RET inhibitors may provide therapeutic benefits in the treatment of RET-positive lung cancer patients.</P>
Chang, Hyun,Rha, Sun Young,Jeung, Hei-Cheul,Im, Chong Kun,Noh, Sung Hoon,Kim, Jin Ju,Chung, Hyun Cheol National Hellenic Research Foundation 2010 ONCOLOGY REPORTS Vol.23 No.1
<P>We evaluated the frequency of ABCB1 polymorphisms (2677G/T>A and 3435C>T) and studied the association between the polymorphisms and clinical outcomes of paclitaxel-based chemotherapy in advanced gastric cancer patients. This study was performed in 43 gastric cancer patients and a control group consisting of 118 healthy volunteers. Patients were treated with paclitaxel combined with an infusional 5-fluorouracil and low-dose leucovorin. Genomic DNA from peripheral blood mononuclear cells was used to determine ABCB1 polymorphisms by direct sequencing. Genotypes were investigated for their association with survival and toxicity. The ABCB1 3435 C allele was more frequent in gastric cancer patients than healthy volunteers (p<0.001). The 2677G>T/A and 3435C>T polymorphisms were independent factors associated with shorter progression-free survival (PFS) (p=0.024, p=0.001, respectively). In combined analysis of 2677 and 3435 polymorphisms, the 3435C>T polymorphism was an independent factor for poor PFS (p=0.01). The 3435CT and TT genotypes were associated with mucositis (p=0.04), and the variant genotypes at 2677 loci were associated with diarrhea (p=0.034). Our data suggest that the ABCB1 polymorphism at 3435 is associated with clinical outcomes after paclitaxel-based combined chemotherapy in advanced gastric cancer patients.</P>
Chang, Hyun,Yang, Yaewon,Lee, Jong-Seok,Jheon, Sang-hoon,Kim, Yu Jung,Chung, Jin-Haeng Elsevier 2019 Clinical lung cancer Vol.20 No.1
<P><B>Abstract</B></P> <P><B>Purpose</B></P> <P>The aim of the present study was to examine the prognostic role of amplification and increased expression of the epidermal growth factor receptor (<I>EGFR</I>) gene in surgically resected non-adenocarcinoma of non-small cell lung cancer (NA-NSCLC).</P> <P><B>Materials and Methods</B></P> <P>The present retrospective study included 114 consecutive NA-NSCLC patients with available tumor tissue and survival data. <I>EGFR</I> gene copy number and protein expression were evaluated using fluorescent in situ hybridization (FISH) and immunohistochemistry in tissue microarray sections, respectively.</P> <P><B>Results</B></P> <P>Among 114 patients, 99 (86.8%) had squamous cell carcinoma histologic features. <I>EGFR</I> gene amplification and high polysomy (<I>EGFR</I> FISH<SUP>+</SUP>) were observed in 7.9% and 31.6% of cases, respectively. Patients with <I>EGFR</I> FISH<SUP>+</SUP> had significantly shorter overall survival (<I>P</I> = .011). A multivariate model confirmed that patients with <I>EGFR</I> FISH<SUP>+</SUP> had a significantly greater risk of death than <I>EGFR</I> FISH<SUP>−</SUP> patients after adjusting for pathologic stage, presence of pleural invasion, venous invasion, and surgical margins (hazard ratio, 1.36; 95% CI, 1.040 to 1.782; <I>P</I> = .025). EGFR protein expression by immunohistochemistry was not associated with overall survival in the same group. Neither <I>EGFR</I> gene amplification nor EGFR immunohistochemistry expression was associated with relapse-free survival.</P> <P><B>Conclusion</B></P> <P>An increased <I>EGFR</I> gene copy number in surgically resected NA-NSCLC was associated with worse survival.</P>
CHANG, HYUN,RHA, SUN YOUNG,JEUNG, HEI-CHEUL,PARK, KYU HYUN,KIM, TAE SOO,KIM, YONG-BAE,CHUNG, HYUN CHEOL Spandidos Publications 2013 International journal of molecular medicine Vol.31 No.5
<P>In this study, we investigated the effects of ionizing radiation (IR) on human umbilical vein endothelial cells (HUVECs) in the context of senescence. HUVECs at passage number (PN)1, PN2 and PN3 were exposed to irradiation (2 Gy). The growth rate of the HUVECS was measured by proliferation assay and senescence-associated β-galactosidase assay was used to measure the number of senescent cells. Telomerase activity and the expression of telomerase- and angiogenesis-related genes were measured by telomerase assay and real-time PCR, respectively. The number of senescent cells was significantly increased in the irradiated HUVECs at all PNs. Compared to the controls, telomerase activity, the expression of human telomerase reverse transcriptase (hTERT) and c-Myc in the irradiated HUVECs were downregulated during serial passage. The downregulation of vascular endothelial growth factor (VEGF) was observed in the irradiated HUVECs as the PN increased. The data presented in this study may aid in the understanding of the mechanisms behind IR?induced EC senescence and telomerase- and angiogenesis?related gene response.</P>
역사소설로서 「취유부벽정기」의 서술 전략 - ‘역사의식’을 중심으로-
김창현 ( Kim¸ Chang-hyun ) 우리어문학회 2022 우리어문연구 Vol.72 No.-
이 글의 목표는 역사소설로서 「취유부벽정기」의 서술 전략을 고찰하는 것이다. 이를 위해 본고는 역사소설의 본질인 ‘역사의식’에 주목하고자 한다. 역사소설의 양식적 미학적 특징들이 모두 역사의식과 관련되어 있기 때문이다. 작가 김시습은 「취유부벽정기」의 배경인 평양을 옛 조선의 도읍으로 규정하고 역사적으로 신성한 공간으로 천명한다. 따라서 여기에 항구적 존재인 기자의 후예가 강림하는 것은 그 신성함을 증명하는 것이다. 작가는 이를 통해 ‘단군-기자-동명왕’이라는 민족적 정통성과 ‘은 탕-조선 기자’라는 이념적 정통성을 동시에 형상화한다. 이렇게 선녀는 김시습의 역사의식이 지닌 이중성과 모순마저 고스란히 간직한 의인화된 역사이다. 이 항구적인 존재인 선녀는 찰나적인 존재인 작가와 동일한 의식을 지닌 영적 연인이기도 하다. 이 영원과 찰나의 대조가 이 작품의 역사의식을 서정화한다. 여기에 역사소설로서 이 작품의 미학적 특징이 있다. 이 작품은 단군과 기자, 동명왕의 사적을 다룬다. 하지만 이 사건들 자체보다 거기에 대한 작가의 해석과 가치평가가 이 작품의 핵심이며, 그것이 이 작품을 높은 수준의 역사적 서사로 만든다. The goal of this article is to study the narrative strategy of < ChwiyuBubyeokjeonggi > as a historical fiction. To this goal, this paper focuses on ‘historical consciousness’, which is the essence of historical fiction. This is because all the stylistic and aesthetic characteristics of this historical novel are related to historical consciousness. The writer, Siseup Kim defines Pyongyang, the background of < ChwiyuBubyeokjeonggi > as the capital of the old Joseon Dynasty, and proclaims it as a historically sacred space. Therefore, the descendant of Gija, who are permanent beings(fairy), descend here to prove the sanctity of this place. Through this, the writer simultaneously embodies the national legitimacy of 'Dangun-Gija-Dongmyeong' and the ideological legitimacy of 'Eun Tang-Joseon Gija'. In this way, the fairy is a personified history that preserves the duality and contradiction of Siseup Kim's historical consciousness. This eternal being, the fairy, is also a spiritual lover with the same consciousness as the writer of the temporary existence. This contrast between eternity and instantaneousness lyricalizes the historical consciousness of this work. Here is the aesthetic characteristic of this work as a historical fiction. This work deals with the historical records of Dangun, Gija, and King Dongmyeong. However, rather than the events themselves, the author's valuing of them is the core of this work, which makes this work a high-level historical narrative.
[CE-0002] Genotype study for heading date using GWAS and genomic selection in wheat core-set
Changhyun Choi(Changhyun Choi),Myoung Hui Lee(Myoung Hui Lee),Urim Kim(Urim Kim),Jin-Kyung Cha(Jin-Kyung Cha),Kyeong-Min Kim(Kyeong-Min Kim),Chon-Sik Kang(Chon-Sik Kang),Jiyoung Son(Jiyoung Son),Jong- 한국육종학회 2022 한국육종학회 공동학술발표집 Vol.2022 No.-