PDGFRA:細(xì)胞信號(hào)傳導(dǎo)的樞紐與疾病治療靶標(biāo)
日期:2025-11-18 17:15:04
血小板源性生長因子受體α(platelet-derived growth factor receptor alpha,PDGFRA)是一種受體酪氨酸激酶,在胚胎發(fā)育、細(xì)胞增殖、遷移和分化過程中發(fā)揮關(guān)鍵作用。其異常激活與多種惡性腫瘤、纖維化及免疫疾病密切相關(guān)。本文系統(tǒng)綜述了PDGFRA的結(jié)構(gòu)特征、信號(hào)機(jī)制、在多種疾病中的作用及靶向藥物的研究進(jìn)展,為進(jìn)一步的基礎(chǔ)研究和精準(zhǔn)治療提供參考。
1. PDGFR的研究背景
血小板源性生長因子受體(PDGFR)屬于受體酪氨酸激酶(RTK)家族,包括PDGFRA和PDGFRB兩個(gè)亞型 [1,2]。其中,PDGFRA主要介導(dǎo)PDGF-AA、PDGF-AB及PDGF-CC等配體信號(hào) [3]。在胚胎發(fā)育過程中,PDGFRA廣泛表達(dá)于間充質(zhì)細(xì)胞、成纖維細(xì)胞及平滑肌祖細(xì)胞中,對(duì)細(xì)胞遷移、組織重塑及血管生成具有重要作用 [4]。
在病理狀態(tài)下,PDGFRA信號(hào)異常被認(rèn)為是多種疾病的關(guān)鍵致病機(jī)制,包括腫瘤、纖維化、動(dòng)脈粥樣硬化及神經(jīng)系統(tǒng)疾病 [5,6]。特別是在胃腸道間質(zhì)瘤(GIST)中,PDGFRA基因突變可導(dǎo)致受體構(gòu)象改變和持續(xù)激活,是繼KIT突變后的另一主要驅(qū)動(dòng)因素 [7]。
2. PDGFRA的結(jié)構(gòu)與功能基礎(chǔ)
2.1 PDGFRA的結(jié)構(gòu)特征
PDGFRA基因位于4q12染色體,編碼約1089個(gè)氨基酸的跨膜糖蛋白,包含五個(gè)免疫球蛋白樣胞外結(jié)構(gòu)域、單一跨膜結(jié)構(gòu)域以及胞內(nèi)酪氨酸激酶結(jié)構(gòu)域 [11]。其中,第3、第4結(jié)構(gòu)域?yàn)榕潴w結(jié)合區(qū),第5結(jié)構(gòu)域參與受體二聚化 [12]。受體活化后,其胞內(nèi)酪氨酸殘基被自磷酸化,為下游信號(hào)通路提供結(jié)合位點(diǎn) [13]。
PDGFRA與PDGFRB結(jié)構(gòu)高度同源,但在配體特異性和信號(hào)轉(zhuǎn)導(dǎo)上存在差異。PDGFRA主要響應(yīng)PDGF-AA、PDGF-AB、PDGF-CC,而PDGFRB則對(duì)PDGF-BB及PDGF-DD更為敏感 [14]。
此外,PDGFRA還與其他受體如FGFR、EGFR存在交叉磷酸化,形成復(fù)雜的信號(hào)調(diào)控網(wǎng)絡(luò) [15]。
2.2 PDGFRA的配體與激活機(jī)制
PDGF家族由四種多肽鏈(A、B、C、D)組成,通過二聚化形成五種異/同源性配體:PDGF-AA、PDGF-BB、PDGF-AB、PDGF-CC、PDGF-DD [16]。這些配體與PDGFR亞型結(jié)合后誘導(dǎo)受體二聚化及自磷酸化,激活下游信號(hào)級(jí)聯(lián)反應(yīng)。
PDGF-AA主要結(jié)合PDGFRA同源二聚體(αα),而PDGF-BB能結(jié)合αα、ββ及αβ復(fù)合體 [17]。PDGF-CC在生理狀態(tài)下需經(jīng)蛋白酶裂解活化,其與PDGFRA結(jié)合后可促進(jìn)細(xì)胞遷移與血管生成 [18]。
受體激活后,PDGFRA胞內(nèi)多個(gè)酪氨酸殘基(如Y572、Y742、Y988、Y1018)被磷酸化,分別與PI3K、PLCγ、Src及Shp2等分子結(jié)合,觸發(fā)多條信號(hào)通路 [19,20]。
2.3 PDGFRA的生理功能
PDGFRA在組織發(fā)育與維持中發(fā)揮重要作用。胚胎期其在神經(jīng)嵴、心臟、肺及腎臟發(fā)育中均不可或缺 [21]。缺失PDGFRA的小鼠表現(xiàn)出嚴(yán)重的發(fā)育缺陷,包括神經(jīng)管畸形和血管生成障礙 [22]。在成人組織中,PDGFRA調(diào)控成纖維細(xì)胞、平滑肌細(xì)胞及肝星狀細(xì)胞等的增殖與遷移 [23]。此外,其參與創(chuàng)傷修復(fù)及細(xì)胞外基質(zhì)沉積 [24]。過度激活的PDGFRA信號(hào)常導(dǎo)致細(xì)胞過度增生與纖維化,是多種慢性疾病的重要病理基礎(chǔ) [25]。
3. PDGFRA的信號(hào)通路
PDGFRA激活后,可通過多條經(jīng)典信號(hào)通路調(diào)控細(xì)胞增殖、分化、遷移與生存。主要包括PI3K/Akt、Ras/MAPK、JAK/STAT及PLCγ等通路。
3.1 PI3K/Akt通路
PI3K/Akt通路是PDGFRA介導(dǎo)的主要生存信號(hào)之一 [26]。受體激活后,PI3K結(jié)合磷酸化的酪氨酸殘基(Y742)并被活化,隨后催化PIP2轉(zhuǎn)化為PIP3,招募Akt至質(zhì)膜并被PDK1磷酸化 [27]。激活的Akt促進(jìn)mTOR、GSK3β及BAD等下游分子磷酸化,從而增強(qiáng)細(xì)胞存活和代謝活性 [28]。在腫瘤細(xì)胞中,PI3K/Akt信號(hào)上調(diào)可抑制細(xì)胞凋亡并增強(qiáng)抗藥性 [29]。此外,PDGFRA-PI3K/Akt信號(hào)還參與纖維母細(xì)胞向肌成纖維細(xì)胞分化,是纖維化形成的關(guān)鍵環(huán)節(jié) [30]。
3.2 Ras/MAPK通路
Ras/MAPK通路主要介導(dǎo)細(xì)胞增殖與遷移信號(hào)。PDGFRA磷酸化的Y988和Y1018可招募Grb2-SOS復(fù)合物,激活Ras-GTP,并依次啟動(dòng)Raf-MEK-ERK級(jí)聯(lián)反應(yīng) [31]。
ERK進(jìn)入細(xì)胞核后促進(jìn)轉(zhuǎn)錄因子AP-1、Elk-1及c-Fos的表達(dá),調(diào)控細(xì)胞周期蛋白(Cyclin D1)轉(zhuǎn)錄,推動(dòng)細(xì)胞從G1期進(jìn)入S期 [32]。研究顯示,PDGFRA的持續(xù)激活可導(dǎo)致MAPK通路過度活躍,引發(fā)細(xì)胞無限增殖,特別是在腫瘤和纖維化組織中 [33]。
3.3 JAK/STAT通路
JAK/STAT信號(hào)是PDGFRA調(diào)控免疫反應(yīng)與細(xì)胞分化的重要途徑。PDGFRA活化后可促進(jìn)JAK1/2磷酸化,從而激活STAT1、STAT3及STAT5 [34]。激活的STAT蛋白進(jìn)入細(xì)胞核,促進(jìn)抗凋亡基因(如Bcl-2、Mcl-1)轉(zhuǎn)錄 [35]。在膠質(zhì)瘤和白血病中,PDGFRA-JAK/STAT信號(hào)上調(diào)與腫瘤細(xì)胞存活密切相關(guān) [36]。
同時(shí),該通路還調(diào)控巨噬細(xì)胞極化及細(xì)胞因子分泌,在慢性炎癥與免疫性疾病中具有重要作用 [37]。
3.4 PLCγ與Ca2?信號(hào)通路
PDGFRA還可激活磷脂酶Cγ(PLCγ)通路。受體的Y1021位點(diǎn)磷酸化后與PLCγ結(jié)合,使其催化PIP2分解為IP3和DAG [38]。IP3誘導(dǎo)內(nèi)質(zhì)網(wǎng)釋放Ca2?,而DAG激活PKC,從而調(diào)控細(xì)胞遷移和收縮功能 [39]。這一通路在血管平滑肌細(xì)胞增殖與遷移中尤為重要,異常激活與動(dòng)脈粥樣硬化、血管重構(gòu)密切相關(guān) [40]。此外,Ca2?信號(hào)還能反饋調(diào)節(jié)PDGFRA磷酸化水平,形成動(dòng)態(tài)平衡機(jī)制 [41]。
3.5 信號(hào)通路的交叉調(diào)控
PDGFRA介導(dǎo)的信號(hào)網(wǎng)絡(luò)高度復(fù)雜,不同通路間存在交叉調(diào)節(jié)。例如PI3K/Akt可通過抑制Raf激活調(diào)控MAPK信號(hào)強(qiáng)度 [42];ERK則能反饋調(diào)節(jié)PDGFRA的磷酸化,限制其過度活化 [43]。
此外,PDGFRA還可與TGF-β、EGFR及VEGFR等通路相互作用,形成多層級(jí)信號(hào)網(wǎng)絡(luò) [44]。在腫瘤微環(huán)境中,這些交叉調(diào)控加劇細(xì)胞生長失控與耐藥性 [45]。
因此,理解PDGFRA相關(guān)通路間的動(dòng)態(tài)互作對(duì)精準(zhǔn)治療具有重要意義。
4. PDGFRA與疾病
PDGFRA的異常激活與多種疾病密切相關(guān),包括惡性腫瘤、纖維化疾病、心血管及神經(jīng)系統(tǒng)疾病等。其作用機(jī)制主要涉及細(xì)胞信號(hào)持續(xù)激活、免疫微環(huán)境改變和細(xì)胞外基質(zhì)重塑。
4.1 PDGFRA與腫瘤
4.1.1 胃腸道間質(zhì)瘤(GIST)
GIST是PDGFRA研究最深入的腫瘤類型之一。約10–15%的GIST攜帶PDGFRA突變,其中最常見的是外顯子18的D842V突變,導(dǎo)致受體持續(xù)激活并對(duì)伊馬替尼耐藥 [46]。阿伐普替尼(avapritinib)作為新型高選擇性抑制劑,可有效靶向D842V突變,顯著改善患者無進(jìn)展生存期 [48]。
4.1.2 膠質(zhì)瘤與腦腫瘤
PDGFRA在膠質(zhì)瘤中高頻擴(kuò)增或過表達(dá),特別是兒童高等級(jí)膠質(zhì)瘤(HGG)[50]。PDGFRA信號(hào)可通過PI3K/Akt和STAT3通路促進(jìn)神經(jīng)膠質(zhì)前體細(xì)胞無限增殖 [51]。
在動(dòng)物模型中,PDGFRA的持續(xù)活化可獨(dú)立驅(qū)動(dòng)腫瘤形成,而聯(lián)合p53缺失則顯著增強(qiáng)惡性程度 [52]。
4.1.3 肺癌與其他實(shí)體瘤
PDGFRA在肺腺癌、結(jié)直腸癌、乳腺癌等多種實(shí)體瘤中亦有異常表達(dá) [55]。其信號(hào)上調(diào)與腫瘤間質(zhì)細(xì)胞激活、血管生成及轉(zhuǎn)移相關(guān) [56]。例如,在非小細(xì)胞肺癌中,腫瘤相關(guān)成纖維細(xì)胞(CAF)分泌PDGF-AA可激活PDGFRA促進(jìn)腫瘤進(jìn)展 [57]。抑制PDGFRA可降低腫瘤細(xì)胞侵襲性并增強(qiáng)免疫治療反應(yīng) [58]。
4.2 纖維化相關(guān)疾病
PDGFRA信號(hào)在多種器官纖維化中被異常激活。其促進(jìn)成纖維細(xì)胞增殖及細(xì)胞外基質(zhì)沉積,是纖維化形成的關(guān)鍵驅(qū)動(dòng)力。在肝纖維化中,PDGFRA通過Akt/mTOR通路促進(jìn)肝星狀細(xì)胞活化與膠原合成 [59]。抑制PDGFRA可顯著減輕肝組織纖維化程度 [60]。在肺纖維化模型中,PDGFRA的上調(diào)導(dǎo)致成纖維細(xì)胞持續(xù)活化;Nintedanib等多靶點(diǎn)TKI通過抑制PDGFRA/FGFR/VEGFR信號(hào)改善疾病進(jìn)程 [61]。
此外,在腎小球硬化及心肌纖維化中,PDGFRA信號(hào)促進(jìn)肌成纖維細(xì)胞分化,增強(qiáng)ECM沉積,形成不可逆組織重塑 [62]。
4.3 心血管系統(tǒng)疾病
PDGFRA在血管發(fā)育及損傷修復(fù)中具有雙重作用。適度激活可促進(jìn)血管平滑肌增殖及再生,而持續(xù)過度激活則引起血管重構(gòu)和粥樣硬化 [47]。研究顯示,PDGFRA信號(hào)通過PLCγ/Ca2?及ERK通路調(diào)節(jié)平滑肌細(xì)胞遷移 [49];其在動(dòng)脈損傷后的過度激活會(huì)導(dǎo)致新生內(nèi)膜形成 [53]。抑制PDGFRA可減少血管平滑肌異常增生并改善再狹窄風(fēng)險(xiǎn) [8]。因此,PDGFRA被認(rèn)為是血管病干預(yù)的重要潛在靶點(diǎn)。
4.4 神經(jīng)系統(tǒng)疾病
PDGFRA在神經(jīng)系統(tǒng)發(fā)育與修復(fù)中同樣重要。其在少突膠質(zhì)前體細(xì)胞(OPC)中表達(dá),對(duì)髓鞘形成和再生至關(guān)重要 [9]。在神經(jīng)損傷或退行性疾病中,PDGFRA信號(hào)調(diào)控神經(jīng)膠質(zhì)細(xì)胞增殖與軸突再生 [10]。然而,過度激活的PDGFRA可能導(dǎo)致異常膠質(zhì)細(xì)胞增生,與神經(jīng)膠質(zhì)瘤形成相關(guān) [54]。因此,維持PDGFRA信號(hào)平衡對(duì)神經(jīng)穩(wěn)態(tài)至關(guān)重要。
5. PDGFRA靶向藥物研究進(jìn)展
目前,針對(duì)PDGFRA靶點(diǎn)的藥物研發(fā)呈現(xiàn)出多元化趨勢(shì),涵蓋了小分子化藥、單克隆抗體、CAR-T細(xì)胞療法等多種類型。如下表所示,除已廣泛批準(zhǔn)用于治療胃腸道間質(zhì)瘤的瑞派替尼、阿伐替尼等多靶點(diǎn)藥物外,更有眾多候選藥物處于不同研發(fā)階段,其適應(yīng)癥已擴(kuò)展至肺動(dòng)脈高壓、特發(fā)性肺纖維化、軟組織肉瘤等多種疾病,展現(xiàn)了該靶點(diǎn)廣闊的臨床開發(fā)前景。
| 藥物 | 靶點(diǎn)(基因名) | 藥物類型 | 在研適應(yīng)癥(疾病名) | 在研機(jī)構(gòu) | 最高研發(fā)階段 |
|---|---|---|---|---|---|
| 瑞派替尼 | PDGFRα x c-Kit | 小分子化藥 | 胃腸道間質(zhì)瘤 | Deciphera Pharmaceuticals, Inc. | Specialised Therapeutics Australia Pty Ltd. | Specialised Therapeutics Asia Pte Ltd. | 再鼎醫(yī)藥(上海)有限公司 | 批準(zhǔn)上市 |
| 阿伐替尼 | PDGFRα x c-Kit | 小分子化藥 | 胃腸道間質(zhì)瘤 | 髓性系統(tǒng)性肥大細(xì)胞增多癥 | 侵襲性系統(tǒng)性肥大細(xì)胞增多癥等 | Blueprint Medicines (Netherlands) BV | Blueprint Medicines Corp. | 基石藥業(yè) | 基石藥業(yè)(蘇州)有限公司 | 批準(zhǔn)上市 |
| 奧拉單抗 | PDGFRα | 單克隆抗體 | X聯(lián)鎖魚鱗病 | 軟組織肉瘤 | 轉(zhuǎn)移性軟組織肉瘤 | 肉瘤 | Telix Pharmaceuticals Ltd. | Eli Lilly & Co. | Eli Lilly Canada, Inc. | 批準(zhǔn)上市 |
| 甲磺酸侖伐替尼 | FGFR1 x FGFR2 x FGFR3 x FGFR4 x PDGFRα x RET x VEGFR1 x VEGFR2 x VEGFR3 x c-Kit | 小分子化藥 | 晚期子宮內(nèi)膜癌 | 復(fù)發(fā)性子宮內(nèi)膜癌 | 胸腺腫瘤 | 晚期腎細(xì)胞癌等 | Eisai, Inc. | Merck Sharp & Dohme Corp. | Merck Sharp & Dohme LLC | AiViva BioPharma, Inc. | Eisai GmbH | Eisai Co., Ltd. | Eisai Europe Ltd. | Beijing Tong Ren Tang (Boryung) Co., Ltd. | MSD Korea Co., Ltd. | 江蘇先聲藥業(yè)有限公司 | 批準(zhǔn)上市 |
| 瑞戈非尼 | BRAF V600E x CRAF x CSF-1R x DDR2 x EphA2 x FGFR1 x FRK x MAPK11 x PDGFRα x PDGFRβ x RET x Tie-2 x TrkA x VEGFR1 x VEGFR2 x VEGFR3 x c-Kit | 小分子化藥 | 肝癌 | 肝細(xì)胞癌 | 結(jié)直腸癌 | 胃腸道間質(zhì)瘤 | 轉(zhuǎn)移性結(jié)直腸癌等 | Merck KGaA | Bayer AG | Bayer HealthCare Pharmaceuticals, Inc. | Bayer Pharma AG | Bristol Myers Squibb Co. | Gustave Roussy, Cancer Campus, Grand Paris | 中山大學(xué) | Amgen, Inc. | Bayer Yakuhin Ltd. | Bayer HealthCare AG | 批準(zhǔn)上市 |
| 培唑帕尼 | FGFR1 x FGFR3 x Flt3L x ITK x LCK x PDGFRα x PDGFRβ x VEGFR1 x VEGFR2 x VEGFR3 x c-Kit | 小分子化藥 | 轉(zhuǎn)移性腎細(xì)胞癌 | 軟組織腫瘤 | 肉瘤 | 腎細(xì)胞癌 | 軟組織肉瘤等 | Novartis AG | Novartis Pharmaceuticals Corp. | Novartis Pharmaceuticals Australia Pty Ltd. | Novartis Europharm Ltd. | GSK Plc | Novartis Pharma KK | Novartis Pharma Schweiz AG | 批準(zhǔn)上市 |
| Seralutinib | CSF-1R x PDGFRα x PDGFRβ x c-Kit | 小分子化藥 | 間質(zhì)性肺病導(dǎo)致的肺動(dòng)脈高壓 | 家族性肺動(dòng)脈高壓 | 特發(fā)性肺動(dòng)脈高壓 | Gossamer Bio, Inc. | CHIESI Farmaceutici SpA | 臨床3期 |
| 甲磺酸馬賽替尼 | LYN x PDGFRα x PDGFRβ x c-Kit | 小分子化藥 | 肌萎縮側(cè)索硬化 | 黑色素瘤 | 轉(zhuǎn)移性結(jié)直腸癌等 | AB Science SA | 臨床3期 |
| Anti-CMV monoclonal antibody(Humabs BioMed SA) | PDGFRα | 單克隆抗體 | 巨細(xì)胞病毒感染 | IRB Barcelona | Humabs BioMed SA | 臨床2期 |
| DCC-3009 | PDGFRα x c-Kit | 小分子化藥 | 胃腸道間質(zhì)瘤 | Deciphera Pharmaceuticals, Inc. | 臨床1/2期 |
| Ansornitinib | DDR1 x DDR2 x PDGFRα x PDGFRβ | 小分子化藥 | 特發(fā)性肺纖維化 | Angion Biomedica Corp. | 臨床1期 |
| ICP-033 | DDR1 x DDR2 x PDGFRα x PDGFRβ x VEGFR2 x VEGFR3 | 小分子化藥 | 局部晚期惡性實(shí)體瘤 | 北京諾誠健華醫(yī)藥科技有限公司 | 臨床1期 |
| 89Zr-TLX300-CDx | PDGFRα | 治療用放射藥物 | 軟組織肉瘤 | Telix Pharmaceuticals Ltd. | 臨床1期 |
| IkT-001Pro | ABL x PDGFRα x PDGFRβ x c-Kit | 小分子化藥 | 慢性期慢性髓性白血病 | 費(fèi)城染色體陽性慢性粒細(xì)胞白血病 | Inhibikase Therapeutics, Inc. | 臨床1期 |
| Ubavitinib | PDGFRα x c-Kit | 小分子化藥 | 晚期癌癥 | 晚期惡性實(shí)體瘤 | 胃腸道間質(zhì)瘤 | 不可切除的黑色素瘤 | 寧波新灣科技發(fā)展有限公司 | 寧波新灣醫(yī)藥科技有限公司 | 臨床1期 |
| Covalent KIT and PDGFRA Inhibitors(TU Dortmund University) | PDGFRα x c-Kit | 小分子化藥 | 胃腸道間質(zhì)瘤 | University of Dortmund | 臨床前 |
| PDGFRA Targeted CAR-T(MD Anderson) | PDGFRα | CAR-T | 膠質(zhì)瘤 | The University of Texas MD Anderson Cancer Center | 臨床前 |
| PDGFR-α inhibitor 6o (China Pharmaceutical University) | PDGFRα | 小分子化藥 | 結(jié)腸癌 | 中國藥科大學(xué) | 臨床前 |
| KIT/PDGFRA抑制劑(塔吉瑞生物) | PDGFRα x c-Kit | 化學(xué)藥 | 急性髓性白血病 | 胃腸道間質(zhì)瘤 | 肥大細(xì)胞增多癥 | 深圳市塔吉瑞生物醫(yī)藥有限公司 | 臨床前 |
| 68Ga-NOTA-CTX004 | PDGFRα | 抗體偶聯(lián)核素 | 診斷用放射藥物 | 胰腺導(dǎo)管腺癌 | Cortalix BV | 臨床前 |
| Compound 22(Shanghai Institute of Materia Medica) | CSF-1R x PDGFRα x SRC family | 小分子化藥 | 特發(fā)性肺纖維化 | 中國科學(xué)院上海藥物研究所 | 臨床前 |
| LQFM-064 | PDGFRα x c-Kit x p53 | 小分子化藥 | 乳腺癌 | Universidade Federal de Goiás | 臨床前 |
| Compound 4p(Sardar Patel University) | PDGFRα | 小分子化藥 | 腫瘤 | Sardar Patel University | 臨床前 |
| 6-Hydroxygenistein | PDGFRα x c-Kit | 小分子化藥 | 胃腸道間質(zhì)瘤 | Mohammed V University | 臨床前 |
(數(shù)據(jù)截止到2025年11月10日,來源于synapse)
6. PDGFRA研究工具
PDGFRA作為重要的受體酪氨酸激酶,在多種生理與病理過程中發(fā)揮核心作用。其異常激活與腫瘤、纖維化、心血管及神經(jīng)疾病密切相關(guān)。華美生物提供PDGFRA重組蛋白、抗體及ELISA試劑盒產(chǎn)品,助力您進(jìn)行相關(guān)機(jī)制研究及靶向藥物開發(fā)。
● PDGFRA重組蛋白
● PDGFRA抗體
● PDGFRA ELISA試劑盒
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