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( Dong-gon Hyun ),( Chang-min Choi ),( Dae Ho Lee ),( Sang-we Kim ),( Shinkyo Yoon ),( Woo Sung Kim ),( Wonjun Ji ),( Jae Cheol Lee ) 대한결핵 및 호흡기학회 2019 대한결핵 및 호흡기학회 추계학술대회 초록집 Vol.127 No.-
Purpose: In patients with epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer (NSCLC) with brain metastases, it remains controversial whether the use of EGFR-tyrosine kinase inhibitor (TKI) alone without radiotherapy (RT) is an optimal approach. Methods: This single-centre retrospective study included a total of 173 patients who were treated with EGFR-TKI alone (TKI group) or with upfront whole-brain RT (WBRT) or stereotactic radiosurgery (SRS) followed by EGFR-TKI (upfront RT group). Clinical outcomes according to initial and subsequent therapies following intracranial progression were analysed. Results: Only intracranial progression was found in 35 (33%) of 107 patients in the TKI group (Figure). Among them, 19 patients received RT, whereas 16 patients could not, mostly due to the deteriorating general condition, leading to the worst prognosis (median overall survival (OS); 28.6 vs. 11.2 months; P = 0.041). In the upfront RT group, 12 (18%) of the 66 patients experienced intracranial progression and 3 of them received salvage RT (median OS; 37.4 vs. 20.0 months; P = 0.044). There was no significant difference in OS according to the use of upfront RT (TKI group, 24.5 months vs. WBRT group, 20.0 months vs. SRS group, 17.8 months; P = 0.186). However, upfront WBRT was associated with trends towards a lower probability of intracranial progression, whereas upfront SRS was found to be an independent risk factor for poor OS in multivariate analysis. Conclusion: Using EGFR-TKI alone for brain metastasis in EGFR-mutant lung cancer patients showed outcomes comparable to those using upfront RT followed by EGFR-TKI. Patients who could not receive salvage RT following intracranial progression had the worst survival regardless of the type of initial treatment.
( Kang-seo Park ),( Yong Sang Hong ),( Junyoung Choi ),( Shinkyo Yoon ),( Jihoon Kang ),( Deokhoon Kim ),( Kang-pa Lee ),( Hyeon-su Im ),( Chang Hoon Lee ),( Seyoung Seo ),( Sang-we Kim ),( Dae Ho Lee 생화학분자생물학회(구 한국생화학분자생물학회) 2018 BMB Reports Vol.51 No.12
Human epidermal growth factor receptor 2 (HER2) inhibitors, such as trastuzumab and lapatinib are used to treat HER2-positive breast and gastric cancers. However, as with other targeted therapies, intrinsic or acquired resistance to HER2 inhibitors presents unresolved therapeutic problems for HER2-positive gastric cancer. The present study describes investigations with AUY922, a heat shock protein 90 (HSP90) inhibitor, in primary lapatinib-resistant (ESO26 and OE33) and lapatinib-sensitive gastric cancer cells (OE19, N87, and SNU-216) harboring HER2 amplification/over-expression. In order to investigate whether AUY922 could overcome intrinsic and acquired resistance to HER2 inhibitors in HER2-positive gastric cancer, we generated lapatinib-resistant gastric cancer cell lines (OE19/LR and N87/LR) by continuous exposure to lapatinib in vitro. We found that activation of HER2 and protein kinase B (AKT) were key factors in inducing intrinsic and acquired lapatinib-resistant gastric cancer cell lines, and that AUY922 effectively suppressed activation of both HER2 and AKT in acquired lapatinib-resistant gastric cancer cell lines. In conclusion, AUY922 showed a synergistic anti-cancer effect with lapatinib and sensitized gastric cancer cells with intrinsic resistance to lapatinib. Dual inhibition of the HSP90 and HER2 signaling pathways could represent a potent therapeutic strategy to treat HER2-positive gastric cancer with intrinsic and acquired resistance to lapatinib. [BMB Reports 2018; 51(12): 660-665]
Seo Ja Young,Ahn Jeong-Yeal,김범석,Kim Miso,Yoon Shinkyo,Lee Jae Lyun,Park Kwonoh,Park Inkeun 대한진단검사의학회 2021 Annals of Laboratory Medicine Vol.41 No.2
Background: Hereditary leiomyomatosis and renal cell cancer (HLRCC) is an autosomal dominant cancer predisposition syndrome. HLRCC is characterized by the development of cutaneous leiomyomas, early-onset uterine leiomyomas, and HLRCC-associated renal cell cancer (RCC) and caused by germline fumarate hydratase (FH) deficiency. We investigated the genotypic and phenotypic characteristics of Korean patients with HLRCC. Methods: We performed direct sequencing analysis of FH in 13 patients with suspected HLRCC and their family members. A chromosomal microarray test was performed in female patients with negative sequencing results but highly suspected HLRCC. In addition, we analyzed the clinical characteristics and evaluated the genotype–phenotype correlations in Korean patients with HLRCC. Results: We identified six different pathogenic or likely pathogenic FH variants in six of the 13 patients (46.2%). The variants included two nonsense variants, two splicing variants, one frameshift variant, and one missense variant. Of the six variants, two (33.3%) were novel (c.132+1G>C, and c.243dup). RCC and early-onset uterine leiomyoma were frequently observed in families with HLRCC, while cutaneous leiomyoma was less common. No significant genotype–phenotype correlation was observed. Conclusions: We describe the genotypic and phenotypic spectrum in a small series of Korean patients with HLRCC. Our data reveal the unique characteristics of Korean patients with HLRCC and suggest a need for establishing an optimal diagnostic approach for them.
Kim, Ji Hye,Nam, Boas,Choi, Yun Jung,Kim, Seon Ye,Lee, Jung-Eun,Sung, Ki Jung,Kim, Woo Sung,Choi, Chang-Min,Chang, Eun-Ju,Koh, Jae Soo,Song, Joon Seon,Yoon, Shinkyo,Lee, Jae Cheol,Rho, Jin Kyung,Son, American Association for Cancer Research 2018 Cancer Research Vol.78 No.16
<P>Enhanced glycolysis by EGFR mutation is required for maintaining EGFR levels via inhibition of JNK-induced autophagy. This provides a promising rationale for use of JNK activators in patients with EGFR-mutated NSCLC.</P><P>Oncogenic EGFR is essential for the development and growth of non–small cell lung cancer (NSCLC), but the precise roles of EGFR in lung cancer metabolism remain unclear. Here, we show that EGFR mutation-mediated enhancement of glycolysis is critical for EGFR stability. EGFR knockdown significantly decreased levels of glycolytic pathway intermediates via transcriptional regulation of glycolytic genes. EGFR mutation-enhanced glycolysis was required for fueling the tricarboxylic acid cycle, a critical component of EGFR stability. Nonsustained ATP production enhanced reactive oxygen species accumulation and subsequent JNK-mediated activation of autophagy, which in turn induced EGFR degradation. Our data show that EGFR-mutant NSCLCs require EGFR mutation-enhanced glycolysis to maintain EGFR stability. This pathway may serve as an attractive therapeutic target for EGFR-mutant NSCLCs.</P><P><B>Significance:</B> Enhanced glycolysis by EGFR mutation is required for maintaining EGFR levels via inhibition of JNK-induced autophagy. This provides a promising rationale for use of JNK activators in patients with EGFR-mutated NSCLC. <I>Cancer Res; 78(16); 4482–96. ©2018 AACR</I>.</P>