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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 鄭永銘 | zh_TW |
dc.contributor.advisor | Yung-Ming Jeng | en |
dc.contributor.author | 邱俐雯 | zh_TW |
dc.contributor.author | Li-Wen CHIOU | en |
dc.date.accessioned | 2023-09-13T16:05:23Z | - |
dc.date.available | 2023-11-09 | - |
dc.date.copyright | 2023-09-13 | - |
dc.date.issued | 2023 | - |
dc.date.submitted | 2023-07-28 | - |
dc.identifier.citation | 1. Margolis B, Skolnik EY. Activation of Ras by receptor tyrosine kinases. J Am Soc Nephrol. 1994;5(6):1288-99.
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/89618 | - |
dc.description.abstract | 美國食品及藥物委員會(US Food and Drug Administration)於2021年核可sotorasib(又名AMG510;商品名為Lumakras)用於治療帶有KRASG12C突變之局部晚期或轉移性非小細胞肺癌(non-small cell lung cancer),為首個被核准供臨床使用之KRASG12C抑制劑。儘管sotorasib在臨床試驗中達到優異的治療成效,這些帶有KRASG12C突變之癌細胞卻可能會在治療後產生抗藥性。大多數針對抗藥機制的研究表示,sotorasib抗藥性起因於癌細胞可藉由重新活化mitogen-activated protein kinase(MAPK)訊息路徑來躲避sotorasib對KRASG12C分子的抑制,因此瞭解參與抗藥性產生的訊息路徑及分子,有助於研擬更有效的治療方針及增進治療成效。
本篇研究中,我們自具有KRASG12C突變之胰臟癌及非小細胞肺癌細胞株建立出sotorasib抗藥性細胞株,並發現這些細胞會持續活化EGFR/PI3K/AKT訊息路徑;因此,若以PI3K抑制劑alpelisib或copanlisib合併sotorasib處理細胞,對於降低細胞存活率有加乘效果;反之,若過度表現持續性活化的PI3K 突變基因或是以shRNA降低PI3K的負調節分子PTEN的表現,則會促進細胞對sotorasib的抗藥能力。 另外,在我們研究抗藥性的過程中意外的發現到:以不含sotorasib的培養基培養抗藥性細胞時,這些細胞會表現出對sotorasib的依存性,因而降低生長速度並造成細胞死亡。在探討此依存性機制的結果中顯示:抗藥性細胞在剝奪sotorasib後會進行由p21Waf1/Cip1介導的生長停滯及由caspase介導的細胞死亡;高度活化的MAPK訊息路徑則會引起嚴重的DNA損傷及複製壓力(replication stress),造成DNA損傷反應(DNA damage response)的活化;持續性的活化MAPK訊息路徑及DNA損傷反應的耗盡會造成細胞過早進入有絲分裂,導致細胞分裂異常並造成微核(micronucleus)及核質橋(nucleoplasmic bridges)產生,進而發生有絲分裂災難(mitotic catastrophe)。若以第一型BRAF抑制物促進MAPK路徑過度活化,則能加劇抗藥性細胞在剝奪sotorasib後的死亡情形,並且在細胞實驗及動物實驗中皆得到證實。 總結而言,我們在本篇研究中證明了KRASG12C突變細胞會藉由活化未受sotorasib抑制的EGFR/PI3K/AKT訊息路徑獲得抗藥性,並闡明抗藥性細胞依存sotorasib的機制。高度活化的MAPK訊息路徑、DNA受損、複製壓力及有絲分裂災難是導致此類抗藥性細胞在剝奪sotorasib後細胞死亡的原因。此外,我們提供了以第一型BRAF抑制劑加劇此sotorasib依存現象的策略,期許為癌症患者提供更好的治療效果。 | zh_TW |
dc.description.abstract | Sotorasib is the first KRASG12C inhibitor approved by the US Food and Drug Administration (FDA) for treating KRASG12C-mutant locally advanced or metastatic non-small-cell lung cancer (NSCLC) in 2021. Clinical trials on the therapeutic use of sotorasib for cancer treatment have reported promising results. However, KRASG12C-mutant cancers can acquire resistance to sotorasib after treatment. Most of the drug resistance mechanisms converge on reactivation of the mitogen-activated protein kinase (MAPK) pathway to bypass KRAS inhibition. Identifying the pathways and molecules involving in the resistance is critical for improving treatment response and developing more effective combination strategies.
We established sotorasib-resistant (SR) cells using KRASG12C-mutant pancreatic cancer and NSCLC cell lines. Our data showed that the epidermal growth factor (EGFR)/phosphoinositide-3 kinase (PI3K)/AKT pathway was constitutively active in SR cells. Therefore, the PI3K inhibitor, alpelisib or copanlisib, in synergy with sotorasib reduced viability of both KRASG12C-mutant cancer cells and their SR sublines. On the contrary, overexpression of constitutively active PI3K mutant or shRNA-mediated knockdown of PTEN in KRASG12C-mutant cancer cells conferred sotorasib resistance. Moreover, during study on the mechanisms underlying sotorasib resistance, we incidentally discovered that when cultured in sotorasib-free medium, SR cells demonstrated a “drug addiction” phenomenon to decrease growth rate and increase cell death. We then investigated the mechanisms underlying sotorasib addiction. In the results, the sotorasib-resistant cells underwent p21Waf1/Cip1-mediated cell cycle arrest and caspase-dependent apoptosis in the absence of sotorasib. Sotorasib withdrawal resulted in robust activation of MAPK pathway, inducing severe DNA damage and replication stress, which activated the DNA damage response (DDR) pathway. Persistent MAPK pathway hyperactivation with DDR exhaustion led to premature mitotic entry and aberrant mitosis, followed by micronucleus and nucleoplasmic bridge formation, resulting in mitotic catastrophe. Pharmacologic activation of the MAPK pathway with a type I BRAF inhibitor could further enhance the effects of sotorasib withdrawal on sotorasib-resistant cancer cells both in vitro and in vivo. Collectively, we identified the EGFR/PI3K/AKT signaling as the bypass activated pathway that mediates sotorasib resistance and elucidated the mechanisms underlying the sotorasib addiction in KRASG12C-mutant cancer cells. Sotorasib addiction appears to be induced by hyperactivation of MAPK pathway, DNA damage, replication stress, and mitotic catastrophe. Furthermore, we devised a therapeutic strategy involving a type I BRAF inhibitor to strengthen the effects of sotorasib addiction; this strategy may provide clinical benefit for patients with cancer. | en |
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dc.description.tableofcontents | 口試委員審定書 I
摘要 II ABSTRACT IV CONTENTS VI I. INTRODUCTION 1 1. KRAS 1 1.1 RAS function and signaling pathway 1 1.2 KRAS mutation 2 1.3 Pancreatic cancer and KRAS 3 1.4 Colorectal cancer and KRAS 4 1.5 Non-small cell lung cancer and KRAS 5 1.6 Sotorasib 6 2. Drug addiction 7 3. Replication stress and mitotic catastrophe 8 3.1 DNA damage response 8 3.2 Replication stress 9 3.3 Mitotic catastrophe 10 4. Aims of the study 11 II. MATERIALS AND METHODS 12 1. Cell culture 12 2. Inhibitor Treatments 12 3. MTT assay and synergism analysis 13 4. Establishment of sotorasib-resistant cells 14 5. Cell Lysate Preparation, Western Blotting, and quantification 15 6. Lentiviral transduction 16 7. RNA interference 17 8. Cell Proliferation Assay 17 9. Annexin V/propidium iodide flow cytometry assay 18 10. Caspase 3 Activity Assay 19 11. BrdU incorporation assay 19 12. CellROX staining 20 13. Immunofluorescence Staining 20 14. γH2AX quantification 21 15. DNA fiber assay 22 16. EdU incorporation assay followed by immunofluorescence 23 17. Comet assay 23 18. Xenografts experiments 24 19. Statistical analysis 25 III. RESULTS 26 1. Activation of EGFR and PI3K confers resistance to sotorasib 26 2. Withdrawal of KRASG12C inhibitor results in the death of sotorasib-resistant KRASG12C-mutant cancer cell. 28 3. MAPK pathway hyperactivation is the mechanism for death of sotorasib-resistant cells after sotorasib withdrawal 30 4. Sotorasib withdrawal induces DNA damage and mitotic catastrophe in sotorasib-resistant cells 31 5. Aggravation of post-sotorasib-withdrawal DNA damage and death in sotorasib-resistant cells by low-dose BRAF inhibitor treatment 35 6. BRAF inhibitor counteracts the tolerance of 65-SR cells to sotorasib withdrawal 36 7. Combination of sotorasib withdrawal and BRAF inhibitor induces tumor regression in vivo 37 IV. DISCUSSION 39 1. Previous studies of resistance to KRASG12C inhibitor 39 2. Previous studies of drug addiction in MAPK-targeting therapy 40 3. Previous studies of toxicity of MAPK hyperactivation 42 3.1 Cell death 42 3.2 DNA damage 43 3.3 Replication stress 44 3.4 Cell cycle arrest 45 4. Previous studies of drug holiday 46 5. Synthetic lethality of KRAS mutation and other driver mutations 47 6. Dual roles of DNA damage in tumorigenesis 47 7. Clinical relevance of drug addiction in cancer therapy 48 7.1 Intermittent treatment of MAPK inhibitor in clinical usage 48 7.2 Pretreatment indicators for drug withdrawal or intermittent treatment 50 8. Conclusion 51 9. Future perspectives 52 V. TABLES 54 Table 1. Antibodies used for Western blotting. 54 Table 2. Antibodies used for immunofluorescence staining. 55 Table 3. STR profiling of MIA PaCa-2 and MIA-SR cells. 56 Table 4. STR profiling of NCI-H23 and H23-SR cells. 57 Table 5. STR profiling of LU65 and 65-SR cells. 58 Table 6. Non-silent genetic variants present in sotorasib-resistant cells but not present in parental cells identified by whole exome sequencing. 59 VI. FIGURES 67 Figure 1. Activation of EGFR/PI3K/AKT pathways confers resistance to sotorasib. 68 Figure 1. (continued) 70 Figure 2. Withdrawal of KRASG12C inhibitor results in the death of sotorasib-resistant KRASG12C-mutant cancer cell. 72 Figure 2. (continued) 73 Figure 3. Hyperactivity of the MAPK signaling pathway causes the sotorasib-addiction phenotype. 75 Figure 4. Sotorasib withdrawal induces DNA damage and replication stress. 77 Figure 4. (continued) 79 Figure 5. Sotorasib withdrawal induces premature mitotic entry and aberrant mitosis. 81 Figure 5. (continued) 83 Figure 6. Inhibition of MAPK pathway prevents DNA damage and reverses nuclear abnormality in sotorasib-resistant cells. 85 Figure 7. Low-dose BRAF inhibitor aggravates sotorasib withdrawal–induced DNA damage and cell death. 87 Figure 7. (continued) 89 Figure 8. BRAF inhibitor sensitizes 65-SR cells to sotorasib withdrawal. 91 Figure 8. (continued) 93 VII. REFERENCES 94 VIII. APPENDIX 107 1. Abbreviation list 107 2. Published papers 109 | - |
dc.language.iso | en | - |
dc.title | KRASG12C突變癌症之sotorasib抗藥性及藥物依存機制 | zh_TW |
dc.title | Mechanisms of sotorasib resistance and addiction in KRASG12C-mutant cancer | en |
dc.type | Thesis | - |
dc.date.schoolyear | 111-2 | - |
dc.description.degree | 博士 | - |
dc.contributor.oralexamcommittee | 葉秀慧;胡春美;楊卿堯;歐大諒;吳恒祥 | zh_TW |
dc.contributor.oralexamcommittee | Shiou-Hwei Yeh;Chun-Mei Hu;Ching-Yao Yang;Da-Liang Ou;Heng-Hsiung Wu | en |
dc.subject.keyword | sotorasib,藥物依存,KRAS,複製壓力,有絲分裂災難, | zh_TW |
dc.subject.keyword | sotorasib,drug addiction,KRAS,replication stress,mitotic catastrophe, | en |
dc.relation.page | 109 | - |
dc.identifier.doi | 10.6342/NTU202302275 | - |
dc.rights.note | 同意授權(全球公開) | - |
dc.date.accepted | 2023-07-31 | - |
dc.contributor.author-college | 醫學院 | - |
dc.contributor.author-dept | 病理學研究所 | - |
顯示於系所單位: | 病理學科所 |
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