本文選題：酪氨酸激酶受體 + 個(gè)性化治療　； 參考：《中國(guó)科學(xué)院大學(xué)(中國(guó)科學(xué)院上海藥物研究所)》2017年博士論文

【摘要】：腫瘤是一種生長(zhǎng)失控的疾病,而酪氨酸激酶受體(RTK)作為主要的生長(zhǎng)信號(hào)受體在腫瘤的發(fā)生發(fā)展中發(fā)揮重要的作用。針對(duì)具有RTK異�；罨�(過(guò)表達(dá)、突變和基因重組等)的腫瘤患者,已有多個(gè)RTK抑制劑(RTKi)用于臨床治療,并且RTK靶向藥物與傳統(tǒng)藥物相比特異性強(qiáng)、安全性高和毒性小。但是,大多數(shù)腫瘤患者在RTK靶向治療3-5個(gè)月后均會(huì)產(chǎn)生耐藥性(獲得性耐藥),并且占據(jù)多數(shù)群體的非RTK基因異�；颊呱踔敛糠諶TK基因異�；颊咴谑状沃委熤芯鶎�(duì)藥物不敏感(原發(fā)性耐藥)。因此,尋找有效的診斷和治療策略成為RTK靶向治療的首要目標(biāo)。RTK的激活需要通過(guò)自身磷酸化實(shí)現(xiàn)。我們通過(guò)RTK酪氨酸磷酸化蛋白芯片檢測(cè)技術(shù),對(duì)10個(gè)組織來(lái)源的62個(gè)腫瘤樣本(細(xì)胞系、移植瘤和組織樣本)進(jìn)行分析,發(fā)現(xiàn)在80%的樣本中存在多個(gè)RTK同時(shí)活化/磷酸化。而利用特異性RTKi同時(shí)靶向多個(gè)活化的RTK可以克服RTKi單藥的耐藥性,誘導(dǎo)G1周期阻滯,有效抑制腫瘤細(xì)胞生長(zhǎng)。RTKi聯(lián)合用藥通過(guò)同時(shí)抑制下游AKT和ERK兩條信號(hào)通路,下調(diào)生長(zhǎng)相關(guān)轉(zhuǎn)錄因子c-MYC的蛋白水平,從而實(shí)現(xiàn)細(xì)胞生長(zhǎng)抑制。腫瘤細(xì)胞的RTK磷酸化圖譜受細(xì)胞自身分泌的內(nèi)源性和環(huán)境提供的外源性促生長(zhǎng)信號(hào)共同調(diào)控。因此,RTKi用藥組合的選擇需要基于實(shí)時(shí)的RTK磷酸化圖譜檢測(cè)。RTK下游信號(hào)蛋白KRAS/BRAF突變的腫瘤細(xì)胞可以不依賴于上游RTK活化,持續(xù)性激活下游AKT和/或ERK通路,促進(jìn)腫瘤發(fā)生和發(fā)展。因此,我們探索了KRAS/BRAF突變的結(jié)直腸癌(CRC)細(xì)胞系中,基于RTK信號(hào)通路的腫瘤個(gè)性化治療策略。結(jié)果表明,KRAS/BRAF突變型CRC細(xì)胞中也存在多個(gè)RTK的同時(shí)活化/磷酸化。上游RTK、下游AKT或MEK抑制劑均不能有效抑制下游AKT和ERK磷酸化,以及抑制突變型腫瘤細(xì)胞生長(zhǎng)。在KRAS/BRAF突變型CRC細(xì)胞中,RTKis只能部分抑制AKT磷酸化,而不抑制ERK磷酸化。AKT抑制劑(AKTi)作用后,活化RTK的磷酸化上調(diào),并通過(guò)RTK-IRS1-PI3K-PDK1途徑誘導(dǎo)AKT的重新激活。MEK抑制劑(MEKi)作用后,發(fā)生不依賴于RTK的CRAF活化介導(dǎo)的ERK重新激活。進(jìn)一步,RTKis和AKTi聯(lián)合用藥可以有效抑制KRAS/BRAF突變型CRC細(xì)胞的AKT磷酸化,協(xié)同抑制腫瘤細(xì)胞的生長(zhǎng)。根據(jù)以上實(shí)驗(yàn)結(jié)果,我們提出一個(gè)基于RTK及其信號(hào)通路的個(gè)性化診斷和治療策略。對(duì)腫瘤細(xì)胞進(jìn)行RTK磷酸化芯片檢測(cè)和下游信號(hào)分子KRAS/BRAF的突變檢測(cè),發(fā)現(xiàn)RTK的磷酸化圖譜和KRAS/BRAF突變情況。針對(duì)只有RTK活化,而不具有KRAS/BRAF突變的腫瘤細(xì)胞,選用相應(yīng)RTKi聯(lián)合用藥進(jìn)行治療;針對(duì)存在RTK活化并且KRAS/BRAF突變的腫瘤細(xì)胞,選擇相應(yīng)的RTKis和AKTi進(jìn)行聯(lián)合用藥治療。
[Abstract]:Tumor is a disease which is out of control. Tyrosine kinase receptor (RTK) plays an important role in tumorigenesis and development as the main growth signal receptor.For cancer patients with abnormal activation of RTK (overexpression, mutation and gene recombination), many RTK inhibitors have been used in clinical treatment, and RTK targeting drugs have higher specificity, higher safety and less toxicity than traditional drugs.However,Most tumor patients develop drug resistance after RTK targeting therapy for 3-5 months (acquired drug resistance, and the majority of patients with non- gene abnormalities or even some patients with RTK gene abnormalities are not treated for the first time)Primary resistance to drugs.Therefore, searching for effective diagnosis and treatment strategy becomes the primary target of RTK targeted therapy. The activation of RTK needs to be achieved by self-phosphorylation.By using RTK tyrosine phosphorylation protein chip technique, 62 tumor samples (cell lines, transplanted tumors and tissue samples) from 10 tissues were analyzed. It was found that multiple RTK were activated / phosphorylated simultaneously in 80% of the samples.Using specific RTKi to target multiple activated RTK at the same time can overcome the drug resistance of RTKi, induce G1 cycle arrest, and effectively inhibit tumor cell growth. RTKi can inhibit both downstream AKT and ERK signaling pathways simultaneously.The protein level of growth-related transcription factor c-MYC was down-regulated to achieve cell growth inhibition.The RTK phosphorylation patterns of tumor cells are regulated by endogenous and environmental exogenous growth-promoting signals.Therefore, the selection of drug combination of RTKi requires that the tumor cells with KRAS/BRAF mutation in the downstream signal protein of .RTK can continuously activate the downstream AKT and / or ERK pathway and promote tumorigenesis and development without relying on upstream RTK activation based on real-time RTK phosphorylation map.Therefore, we explored the personalized treatment strategy based on RTK signaling pathway in KRAS/BRAF mutant colorectal cancer cell lines.The results showed that multiple RTK were simultaneously activated / phosphorylated in KRAS-BRAF mutant CRC cells.Neither upstream nor downstream AKT or MEK inhibitors could effectively inhibit downstream AKT and ERK phosphorylation and inhibit the growth of mutant tumor cells.In KRAS/BRAF mutant CRC cells, AKT phosphorylation was partially inhibited, but not inhibited by ERK phosphorylation. AKT inhibitor, Akti, increased the phosphorylation of RTK and induced AKT reactivation via RTK-IRS1-PI3K-PDK1 pathway.ERK reactivation was induced by CRAF activation independent of RTK.Furthermore, the combination of rtkis and AKTi can effectively inhibit the AKT phosphorylation of KRAS/BRAF mutant CRC cells and synergistically inhibit the growth of tumor cells.Based on the above experimental results, we propose a personalized diagnosis and treatment strategy based on RTK and its signal pathway.The phosphorylation patterns and KRAS/BRAF mutations of RTK were detected by RTK phosphorylation microarray and mutation detection of downstream signal molecule KRAS/BRAF.For tumor cells with only RTK activation but no KRAS/BRAF mutation, the corresponding RTKi combination therapy was used to treat the tumor cells with RTK activation and KRAS/BRAF mutation, and the corresponding RTKis and AKTi were selected to treat the tumor cells with RTK activation and KRAS/BRAF mutation.
【學(xué)位授予單位】：中國(guó)科學(xué)院大學(xué)(中國(guó)科學(xué)院上海藥物研究所)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2017
【分類號(hào)】：R73-3

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