臺灣博碩士論文加值系統

上皮細胞生長因子接受體酪酸酶抑制劑(EGFR-TKI)對於有基因突變的非小細胞肺癌患者有療效，特別是EGFR exon 19出現基因缺失(delE746-A750)以及在exon 21出現L858R 點突變等兩種突變。在台灣，使用EGFR-TKI (gefitinib或erlotinib)藥物治療具EGFR突變之肺腺癌患者，高達60-80%患者的腫瘤會縮小。然而，另外的20-40%患者的腫瘤雖有突變，卻仍有抗藥性。而且，即使EGFR-TKI一開始對腫瘤有療效，但治療8-12月後仍會產生抗藥性。因此我們需要正視TKI的抗藥性問題，有研究證實50%的抗藥性與腫瘤發生T790M的續發突變有關，而針對T790M突變如今亦有第三代EGFR-TKI藥物可以改善。然而，EGFR-TKI的抗藥性機制至今仍未被完全了解。

我們利用臨床取得的腫瘤組織檢體進行初代培養，成功建立ㄧ株具有L858R基因突變，卻對gefitinib有抗藥性的細胞株JLR10。這個細胞株沒有已知的T790M的續發突變，也沒有KRAS 或BRAF基因突變。而EGFR除了TK domain外，在exon 13位置有發現R521K的點突變。JLR10具有c-MET與EGFR基因放大，可活化PI3K及MAPK訊息傳遞路徑。JLR10可提供一個讓我們研究TKI抗藥機制的好機會。

為了尋找可能的TKI抗藥機轉，我們利用Affymetrix CytoScan HD/750k array分析比對JLR10 (L858R, gefitinib-resistant)與H3255 (L858R, gefitinib-sensitive)細胞株的基因組態，發現只有JLR10在X染色體位置45,364,927到48,721,997有基因放大，包括miR-221與miR-222，有研究顯示gefitinib可以藉由降低miR-221與miR-222表達來促使肺癌細胞凋亡。miR-221/222的標的基因為PTEN、TRAIL等細胞凋亡基因，miR-221/222的高表達也被報導與TRAIL抗藥性有關，因此此兩株細胞株可能具不同抗藥機轉，會是研究以TRAIL為基礎的合併藥物治療肺癌的好工具。

我們利用MTT、crystal violet、Annexin-V/PI、cell cycle analysis、ELISA以及western blotting等方法學分析單一藥物或合併TRAIL對於JLR10細胞的抑癌效果。結果顯示MET抑制劑PHA665257單獨使用或合併gefitinib顯示可以抑制JLR10細胞生長、降低磷酸化蛋白的表現，並使細胞停滯於細胞週期的G1-S期，但合併TRAIL使用時卻無顯著加乘效果；而單獨使用多激酶抑制劑sorafenib或TRAIL雖無明顯抑癌效果，但兩種藥物合併使用卻可以顯著的降低細胞存活率，誘發細胞凋亡，並顯著抑制荷瘤小鼠的腫瘤生長。這些研究結果顯示合併TRAIL與sorafenib可以引起大於加乘的抑癌效果，提供了以TRAIL為基礎之合併治療非小細胞肺癌的新契機。
我們先前研究發現4-gene signature與早期非小細胞肺癌患者的預後有關，進一步研究發現腫瘤組織的RAB38基因高表達與患者疾病復發及整體存活期有高度關聯，是肺癌的預後因子。我們也發現RAB38基因的高表達與EGFR基因突變有正相關，在RAB38基因剔除的肺癌細胞株中更發現細胞侵入能力明顯受到抑制。因此RAB38可能與EGFR基因突變有關，有機會作為治療肺癌轉移的標靶分子。

利用臨床腫瘤檢體及肺癌細胞株，我們證實RAB38是肺癌的預後因子，且合併TRAIL與sorafenib可以快速並顯著誘發肺癌細胞株凋亡。而microRNA影響TRAIL調節細胞凋亡誘發基因的表現是肺癌對標靶藥物產生抗藥性的可能機制則仍需更多研究來證實。

Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) are effective therapies for patients with non-small cell lung cancer (NSCLC) bearing EGFR mutations. It is reported that the response rate is 60-80% in Taiwan. Despite bearing EGFR active mutations, 20-40% of patients did not respond to TKIs. Moreover, in certain patients responding to TKIs initially, drug resistance will develop in 8-12 months after treatment. An acquired T790M mutation was detected in half of TKI-resistant tumors and the third-generation EGFR inhibitors, osimertinib, was demonstrated to show activity against this mutation. Nevertheless, the resistant mechanisms are still not fully understood.

We have successfully cultivated an NSCLC cell line, JLR10, bearing L858R mutation and exhibiting resistance to gefitinib. JLR10 expressed wild type in KRAS and BRAF genes; no mutation in EGFR other than TK domain was found, but a variant of exon 13 (R521K) was observed. JLR10 expressed MET gene amplification, accompanied with constitutive activation of both PI3K and MAPK pathways. This cell line could serve as a good model to explore novel resistant genes in NSCLC.

In searching for potential genes relevant to EGFR-TKI resistance, the genetic profiles of JLR10 (L858R, gefitinib-resistant) and H3255 (L858R, gefitinib-sensitive) were analyzed with Affymetrix CytoScan HD/750k array and compared. The results showed that while both miR221 and miR222 were highly expressed in JLR10, they were negligible in the latter, a good correlation with MET expression in these 2 cell lines. Upregulation of miR221/222 has been reported to be associated with TRAIL resistance. Our drug sensitivity experiments, however, demonstrated that while H3255 was completely resistant to TRAIL, it induced a moderate cell death in JLR10, suggesting the existence of differential resistant mechanisms in these two cell models.

The antitumor activity of combining TRAIL with available small molecular inhibitors was then evaluated. MET inhibitor PHA665257 significantly inhibited autophosphorylation of MET, AKT and ERK1/2 in JLR10 but did not synergize with TRAIL to induce tumor cell death. Unexpectedly, sorafenib, a multikinase inhibitor, although not exhibiting tumor inhibitory activity alone, demonstrated a high synergistic effect with TRAIL to induce cell apoptosis in JLR10; whereas, all available EGFR mutated NSCLC cell lines were resistant to this combined treatment. The synergistic effect can even be observed shortly (6-h) after treatment. These results suggest that combined sorafenib and TRAIL treatment could represent a potential therapeutic in NSCLC.

Previously we have reported that a four-gene signature (LCN2, PTHLH, FJX1, and RAB38) was associated with survival among patients with early-stage NSCLC. Our subsequent studies showed that higher RAB38 expression in tumor specimens was associated with higher frequency of tumor recurrence in these patients; RAB expression was also inversely correlated with disease-free survival and overall patient survival, suggesting that it may serve as a prognostic factor in NSCLC. Using NSCLC cell lines, we further demonstrated that tumor cells with EGFR mutations expressed higher levels of RAB38 compared with those of wild-type. Furthermore, following specific knockdown of RAB38 by shRNA transfection, substantially reduced Matrigel invasiveness was detected in HCC827 cells (Exon 19 deletion) compared to those transfected with empty vector. These results indicate that RAB38 may be associated with EGFR status and could be targeted to reduce tumor metastasis in NSCLC.

Using clinical specimens and in vitro cell models, we have shown that RAB38 could serve as a potential target in NSCLC and combination of sorafenib and TRAIL treatment induced a rapid and substantial cell apoptosis in NSCLC cell line. Although the mechanisms associated with these observations remain to be explored, these studies may pave the way toward effective treatment for this deadly disease.

Table of Contents

謝誌 -----------------------------------------------------------------------------------------------I
摘要 ----------------------------------------------------------------------------------------------II
Abstract -----------------------------------------------------------------------------------------IV
Table of Contents ------------------------------------------------------------------------------VI
List of Figures --------------------------------------------------------------------------------VIII
List of Tables ----------------------------------------------------------------------------------X
List of Abbreviations ------------------------------------------------------------------------XI
Chapter 1. Bibliography reviews --------------------------------------------------------------1
1.1 Cell signaling networks and tumorigenesis ---------------------------------------1
1.2 Gene alterations and molecular targeted therapy --------------------------------1
1.3 Resistance mechanisms of EGFR targeted therapy ------------------------------2
1.4 Overcome the resistance of EGFR-TKIs ------------------------------------------3
Chapter 2. Precision medicine for optimal outcomes ---------------------------------------5
2.1 Background ----------------------------------------------------------------------------5
2.1.1 Genetic alterations in non-small cell lung cancer -----------------------------5
2.1.2 Genomic signatures and predictively clinical outcomes ---------------------7
2.2 Experimental design ------------------------------------------------------------------8
2.3 Results and discussion ---------------------------------------------------------------9
Chapter 3. Prognostic factors and therapeutic strategies ---------------------------------12
3.1 Background --------------------------------------------------------------------------12
3.1.1 Prognostic factors for NSCLC -------------------------------------------------12
3.1.2 Prognostic factors and therapeutic targets ------------------------------------13
3.2 Materials and methods --------------------------------------------------------------14
3.3 Results and discussion --------------------------------------------------------------17
Chapter 4. Enhancement of antitumor efficiency via available drugs and/or combined
drug treatment --------------------------------------------------------------------20
4.1 Background -------------------------------------------------------------------------20
4.1.1 Identification of genetic profile via a newly established NSCLC line ---20
4.1.2 Potential therapeutic drugs -----------------------------------------------------21
4.2 Materials and methods --------------------------------------------------------------24
4.3 Results and discussion --------------------------------------------------------------31
4.3.1 JLR10 expressed wild type in EGFR other than TK domain --------------31
4.3.2 Amplification of nucleotides on chr.7 and down-regulation of nucleotides
on chr.22 were observed in JLR10 cell line compared to normal lung tissue
---------------------------------------------------------------------------------------31

4.3.3 Gain of copy number on chromosome Xp11.3 in JLR10, but loss in
H3255 ----------------------------------------------------------------------------32
4.3.4 Short-term gemcitabine treatment did not induce cell death in
EGFR-mutant NSCLC ---------------------------------------------------------33
4.3.5 Gemcitabine and bortezomib induced cell-cycle arrest and apoptosis ---33
4.3.6 Gemcitabine and bortezomib decreased ERK1/2 activation and increased
hIL-6 secretion ------------------------------------------------------------------34
4.3.7 c-MET inhibitor PHA665257 show anti-tumor effects in a dose-dependent
manner ----------------------------------------------------------------------------34
4.3.8 Bortezomib treatment reduced serum levels of human cytokines in
cachectic nude mice ------------------------------------------------------------35
4.3.9 Sorafenib plus TRAIL show a synergistic effect of the inhibition of cell
survival in vitro and in vivo ----------------------------------------------------36
Chapter 5. Conclusion and future directions -----------------------------------------------38
Chapter 6. References -------------------------------------------------------------------------41
 

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