항암제 개발: 토포아이소머라제, HSP90, mTOR 및 티로신키나제 억제제

최경철(Kyoungcheol Choi),이성호(Seongho Lee),권미지(Miji Kwon),홍세영(Seyoung Hong),박희호(Hee Ho Park),임광석(Kwang Suk Lim) 한국생물공학회 2021 KSBB Journal Vol.36 No.2

Chemical anticancer drugs that have been used for a long time for the treatment of cancer have high anticancer effects and many side effects. The side effects of anticancer drugs have also affected normal cells because they induce the death of cancer cells by inhibiting or blocking essential mechanisms for cell survival. Recently, inhibitory drugs that inhibit specific mechanisms of cancer cells are receiving a lot of attention as anticancer drugs. Inhibitory drugs have less effect on normal cells by inhibiting the activity of target proteins that are overexpressed in cancer cells. Representative anticancer inhibitors among many inhibitory drugs are mTOR inhibitors, topoisomerase inhibitors, heat shock protein 90 (HSP90) inhibitors and tyrosine kinase inhibitors. For each of these inhibitor family, new candidate inhibitor drugs are continuously being developed and clinical trials are underway. In this review, we will examine the drug mechanism of each inhibitor drug, and describe the approved drugs and drugs in clinical trials.

방사성요오드 불응성 갑상선암에서 티로신키나아제 억제제 투여로 유발된 중증 피로감의 관리

안병철 대한갑상선학회 2018 International Journal of Thyroidology Vol.11 No.2

Tyrosine kinase inhibitor is known to prolong progression free survival in radioiodine refractory thyroid cancer patients. Fatigue/asthenia/malaise is one of most common adverse events by the tyrosine kinase inhibitor treatment, and management of the adverse event is important to keep the drug medication longer which is essential for the survival benefit. In the case report, a radioiodine refractory thyroid cancer patient receiving tyrosine kinase inhibitor experienced severe fatigue, and a pathologic fracture of right humerus occurred by slipping down which was tightly linked with the adverse event of the drug. The pathologic fracture was surgically well managed and the adverse event was well controlled by supportive managements combined with dose reduction of the tyrosine kinase inhibitor. The drug administration to the patient was kept more than 1 year without progression of the disease.

EGF Induced RET Inhibitor Resistance in CCDC6-RET Lung Cancer Cells

장현,성지혜,문승욱,김한수,김진원,이종석 연세대학교의과대학 2017 Yonsei medical journal Vol.58 No.1

Purpose: Rearrangement of the proto-oncogene rearranged during transfection (RET) 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 RET 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 hepatocytegrowth factor (HGF) trigger RET inhibitor resistance in LC-2/ad cells with CCDC6-RET fusion genes. Materials and Methods: The effects of EGF and HGF on the susceptibility of a CCDC6-RET lung cancer cell line to RET inhibitors (sunitinib, E7080, vandetanib, and sorafenib) were examined. Results: CCDC6-RET 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. Endothelialcells, which are known to produce EGF, decreased the sensitivity of CCDC6-RET 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. Conclusion: EGF could trigger resistance to RET inhibition in CCDC6-RET lung cancer cells, and endothelial cells may confer resistanceto RET inhibitors by EGF. E7080 and other RET inhibitors may provide therapeutic benefits in the treatment of RET-positivelung cancer patients.

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>

Acquired Resistance of MET-Amplified Non-small Cell Lung Cancer Cells to the MET Inhibitor Capmatinib

김슬기,김태민,김동완,김소연,김미소,안용운,김범석,허대석 대한암학회 2019 Cancer Research and Treatment Vol.51 No.3

Purpose Amplified mesenchymal-epithelial transition factor, MET, is a receptor tyrosine kinase (RTK) that has been considered a druggable target in non-small cell lung cancer (NSCLC). Although multiple MET tyrosine kinase inhibitors (TKIs) are being actively developed for MET-driven NSCLC, the mechanisms of acquired resistance to MET-TKIs have not been well elucidated. To understand the mechanisms of resistance and establish therapeutic strategies, we developed an in vitro model using the MET-amplified NSCLC cell line EBC-1. Materials and Methods We established capmatinib-resistant NSCLC cell lines and identified alternative signaling pathways using 3! mRNA sequencing and human phospho-RTK arrays. Copy number alterations were evaluated by quantitative polymerase chain reaction and cell proliferation assay; activation of RTKs and downstream effectors were compared between the parental cell line EBC-1 and the resistant cell lines. Results We found that EBC-CR1 showed an epidermal growth factor receptor (EGFR)–dependent growth and sensitivity to afatinib, an irreversible EGFR TKI. EBC-CR2 cells that had overexpression of EGFR-MET heterodimer dramatically responded to combined capmatinib with afatinib. In addition, EBC-CR3 cells derived from EBC-CR1 cells that activated EGFR with amplified phosphoinositide-3 kinase catalytic subunit " (PIK3CA) were sensitive to combined afatinib with BYL719, a phosphoinositide 3-kinase " (PI3K") inhibitor. Conclusion Our in vitro studies suggested that activation of EGFR signaling and/or genetic alteration of downstream effectors like PIK3CA were alternative resistance mechanisms used by capmatinib- resistant NSCLC cell lines. In addition, combined treatments with MET, EGFR, and PI3K" inhibitors may be effective therapeutic strategies in capmatinib-resistant NSCLC patients.

Targeting tyrosine kinases for treatment of ocular tumors

Dong Hyun Jo,Jin Hyoung Kim,Jeong Hun Kim 대한약학회 2019 Archives of Pharmacal Research Vol.42 No.4

Uveal melanoma is the most common intraocular primary malignant tumor in adults, and retinoblastoma is the one in children. Current mainstay treatment options include chemotherapy using conventional drugs and enucleation, the total removal of the eyeball. Targeted therapies based on profound understanding of molecular mechanisms of ocular tumors may increase the possibility of preserving the eyeball and the vision. Tyrosine kinases, which modulate signaling pathways regarding various cellular functions including proliferation, differentiation, and attachment, are one of the attractive targets for targeted therapies against uveal melanoma and retinoblastoma. In this review, the roles of both types of tyrosine kinases, receptor tyrosine kinases and non-receptor tyrosine kinases, were summarized in relation with ocular tumors. Although the conventional treatment options for uveal melanoma and retinoblastoma are radiotherapy and chemotherapy, respectively, specific tyrosine kinase inhibitors will enhance our armamentarium against them by controlling cancer-associated signaling pathways related to tyrosine kinases. This review can be a stepping stone for widening treatment options and realizing targeted therapies against uveal melanoma and retinoblastoma.

비소세포폐암 환자에 있어서 Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors의 약효 및 rash 발생과 관련한 인자에 대한 연구

배나래,최혜진,이병구,곽혜선 이화여자대학교 약학연구소 2009 藥學硏究論文集 Vol.- No.19

Purpose: Currently lung cancer ranks second in cancer for incidence rate and is a disease that ranks first for a death rate by cancerous growth because it is already advanced at the time of diagnosis. The purpose of this paper was to analyze the factors that affect the effectiveness of and rash occurrence by Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor (EGFR TKI) in patients with non-small cell lung cancer. Methods: A retrospective chart review of 100 patients, who took EGFR TKI (erlotinib, gefitinib) among patients who were diagnosed with non-small cell lung cancer in a Hospital in Korea between May 2005 and February 2008, was conducted. The drug effectiveness was evaluated by Response Evaluation Criteria In Solid Tumor. Results: EGFR mutation was the only factor associated with drug response (complete response and partial response). When stable disease was added to drug response as the evaluation parameter, ECOG and rash as well as EGFR mutation were found to be important factors. Survival, however, was not affected by EGFR mutation. The factors influenced on survival were older age (≥65), low ECOG (1~2), adenocarcinoma and rash. In the case of rash, group with EGFR mutation or low ECOG showed significantly higher chance of occurrence. There was no significant difference in rash occurrence between gefitinib and erlotinib groups. Conclusions: Based on the results, EGFR mutation positive and low ECOG (1~2) were significantly important factors for both effectiveness of EGFR TKI and rash occurrence. Also, rash itself was found to be an independently significant factor for the disease control and survival. Therefore, while administering EGFR TKI, patients who have the factors associated with rash occurrence should be closely monitored for effective and safe drug therapy.

Anti-cancer Effects of Polyphenolic Compounds in Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor-resistant Non-small Cell Lung Cancer

Jeong, Hyungmin,Phan, Ai N. H.,Choi, Jong-Whan Medknow PublicationsMedia Pvt Ltd 2017 Pharmacognosy magazine Vol.13 No.52

<P><B>Background:</B></P><P>Polyphenolic phytochemicals are natural compounds, easily found in fruits and vegetables. Importantly, polyphenols have been intensively studied as excellent antioxidant activity which contributes to anticancer function of the natural compounds. Lung cancer has been reported to mainly account for cancer-related deaths in the world. Moreover, epidermal growth factor receptor tyrosine kinase inhibitor (TKI) resistance is one of the biggest issues in cancer treatment, especially in nonsmall cell lung cancer (NSCLC). Even though several studies both in preclinical and clinical trials have showed promising therapeutic effects of polyphenolic compounds in anticancer therapy, the function of the natural compounds in TKI-resistant (TKIR) lung cancer remains poorly studied.</P><P><B>Objective:</B></P><P>The aim of this study is to screen polyphenolic compounds as potential anticancer adjuvants which suppress TKIR lung cancer.</P><P><B>Materials and Methods:</B></P><P>Colony formation and thiazolyl blue tetrazolium blue assay were performed in the pair-matched TKI-sensitive (TKIS) versus TKIR tumor cell lines to investigate the therapeutic effect of polyphenolic compounds in TKIR NSCLC.</P><P><B>Results:</B></P><P>Our data show that equol, kaempferol, resveratrol, and ellagic acid exhibit strong anticancer effect in HCC827 panel. Moreover, the inhibitory effect of most of tested polyphenolic compounds was highly selective for TKIR lung cancer cell line H1993 while sparing the TKIS one H2073.</P><P><B>Conclusion:</B></P><P>This study provides an important screening of potential polyphenolic compounds for drug development to overcome TKI resistance in advanced lung cancer.</P><P><B>SUMMARY</B></P><P><P>The study provides an important screening of potential polyphenolic compounds for drug development to overcome tyrosine kinase inhibitor (TKI) resistance in advance lung cancer</P><P>Equol, kaempferol, resveratrol, and ellagic acid show strong anticancer effect in HCC827 panel, including TKI-sensitive (TKIS) and TKI-resistant clones</P><P>The inhibitory effect of polyphenolic compounds such as equol, kaempferol, resveratrol, ellagic acid, gallic acid, p-Coumaric, and hesperidin is highly selective for TKI-resistant lung cancer cell line H1993 while sparing the TKIS one H2073.</P></P><P>[GRAPHIC OMISSION]</P><P><B>Abbreviations used:</B> EGFR: Epidermal growth factor receptor, EMT: Epithelial-to-mesenchymal transition, GTP: Green tea polyphenols, IGF1R: Insulin-like growth factor 1 receptor, MET: Met proto-oncogene, MTT: Thiazolyl blue tetrazolium blue, NSCLC: Non-small cell lung cancer, ROS: Reactive oxygen species, RTK: Receptor tyrosine kinase, STAT3: Signal transducer and activator of transcription 3, TKIR: TKI-resistant, TKIs: Tyrosine kinase inhibitors, TKIS: TKI-sensitive.</P>

Clinical Characteristics and Outcomes of TFE3-Rearranged/TFEB-Altered Renal Cell Carcinoma with Systemic Therapies, Including Tyrosine Kinase Inhibitors or Immune Checkpoint Inhibitors: An Observational Study

홍주현,Ghee Young Kwon,강민용,서성일,박세훈 대한비뇨기종양학회 2024 대한비뇨기종양학회지 Vol.22 No.1

Purpose: TFE3-rearranged/TFEB-altered renal cell carcinoma (RCC) is a rare subtype of RCC. Due to its rarity, there is an unmet medical need for effective therapies in advanced settings. The study aims to investigate the clinical and histopathological characteristics of patients with microphthalmia transcription factor family/ transcription factor E (MiTF/TFE) translocation RCC and the clinical outcomes of systemic therapies, including tyrosine kinase inhibitors (TKIs) or immune checkpoint inhibitors (ICIs). Materials and Methods: This was a single-center, retrospective study. We identified 32 eligible patients among a total of 37 patients diagnosed with MiTF/TFE translocation RCC between January 2004 and September 2021, and the study included 9 patients who were treated with systemic therapies. We collected data on clinical characteristics, targeted sequencing, and clinical outcomes. Results: The median age of the 32 patients was 45.5 years. Histologically, 26 patients (81.3%) had TFE3- rearranged RCC, and only 1 patient (3.1%) had TFEB-altered RCC. Curative or cytoreductive nephrectomy was performed in all 27 patients (84.4%), and 4 patients (12.6%) were diagnosed with metastatic disease at the time of the initial diagnosis. Nine patients (28.1%) were treated with systemic therapy with TKIs, 2 (6.3%) of whom received simultaneous TKI and ICI treatment. The response to systemic therapy (TKI or ICI) and duration of response ranged from complete response to progressive disease. Excluding 1 patient who was treated with a TKI in the adjuvant setting, the overall response rate in 8 metastatic patients was 50% and the complete response rate was 37.5%. The median follow-up period was 29 months. The median progressionfree survival was 21 months, median overall survival was not achieved, and 2 deaths occurred. Conclusions: Our findings suggest that TKI for treatment for metastatic TFE3-rearranged RCC is efficacious, with an overall response rate of 50% and a median progression-free survival of 21 months.

Synthesis and biological evaluation of anilide derivatives as epidermal growth factor receptor L858R / T790M and L858R / T790M / C797S inhibitors

Kim Soo Lim,Yang Yo‐Sep,Lee Sujin,Kim Nam‐Jung 대한화학회 2022 Bulletin of the Korean Chemical Society Vol.43 No.8

Development of a mutant epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor is important for the treatment of various cancers. Thirdgeneration EGFR tyrosine kinase inhibitors (TKIs) have been clinically used by targeting T790M specifically but are recently known to induce T790M/C797S mutation after the treatment. Therefore, there is an unmet need to develop novel kinase inhibitors targeting the mutant EGFRs. Here, we designed and synthesized 16 analogs by hybridizing EAI045 (1) and 30 ,40,50-trihydroxyflavone (2) and identified 9a, 9b, and 20b as EGFR L858R/T790M/C797S mutant inhibitors. In addition, we found that 10a and 10b can inhibit both L858R/T790M and L858R/T790M/C797S. Molecular docking study on a plausible binding mode of the compounds is also provided.