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Nan Fang Yi Ke Da Xue Xue Bao.
2020 Oct 20; 40(10): 1448–1456.
Language:
Chinese
|
English
帕那替尼对内源性表达FGFR2-CCDC6融合蛋白的人胆管癌异种移植小鼠的抗肿瘤作用
Ponatinib inhibits growth of patient-derived xenograft of cholangiocarcinoma expressing FGFR2-CCDC6 fusion protein in nude mice
吴 天宇
南方医科大学南方医院肝胆外科，广东 广州 510515,
Department of Hepatobiliary Surgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
蒋 晓青
南方医科大学南方医院重症医学科，广东 广州 510515,
Surgical Intensive Care Unit, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
徐 斌
南方医科大学南方医院肝胆外科，广东 广州 510515,
Department of Hepatobiliary Surgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
王 宇
南方医科大学南方医院肝胆外科，广东 广州 510515,
Department of Hepatobiliary Surgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
南方医科大学南方医院肝胆外科，广东 广州 510515,
Department of Hepatobiliary Surgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
南方医科大学南方医院重症医学科，广东 广州 510515,
Surgical Intensive Care Unit, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
(p13)x2，idic(1)(p13)，del(3)(p13p21)，del(4)(q21)，del
K
)。通过断裂分析和G显带也证明了LIV31中的FGFR2存在融合。LIV31细胞系的G-带状核型为48，XX，+add(1)
(p13)x2，idic(1)(p13)，del(3)(p13p21)，del(4)(q21)，del (6)(q13q25)，-9，-10，-10，dup(12)(q13q15)，add(14)
(q32)，add(15)(p11.2)，+20，+2mar(
)。而应用FGFR2 BAC和D10Z1探针的LIV31细胞系显示出两条衍生染色体10 s，一条丢失了3'FGFR2，另一条重排了FGFR2基因(
)。应用全染色体涂10探针的LIV31在细胞系图像显示，衍生染色体10 s中的一条完全由10号染色体组成，另一条由染色体10与一条未知染色体间的不平衡易位有关(
)。
2.2. 帕那替尼显著抑制LIV31异种移植瘤的生长
有研究表明
[
19
]
，在一个具有FGFR2过表达的胃癌模型中，用30 mg/kg的帕那替尼治疗小鼠，可导致小鼠皮肤出现脱落，而将帕那替尼的剂量降低到20~25 mg/kg时，小鼠皮肤未出现不良反应。故本实验将帕那替尼的剂量定在20 mg/kg。与用赋形剂治疗的对照小鼠相比，单独以20 mg/kg/d的帕那替尼剂量口服管饲小鼠，显著降低了其肿瘤生长(
P
< 0.0001)(
、
)。在治疗的第63天，帕那替尼治疗小鼠的肿瘤体积明显小于用载体治疗的对照组小鼠，平均肿瘤体积分别为619.3± 119.5 mm
3
和1417±206.3 mm
3
。存活曲线显示单独使用帕那替尼治疗后存活率显著提高(通过肿瘤体积 < 400 mm的小鼠数量评估，
)。在治疗结束时，用帕那替尼治疗的9只小鼠中有4只(44%)的肿瘤体积小于400 mm，而用载体治疗的10只小鼠中没有一只的肿瘤体积小于400 mm(
P
< 0.05，
)。各组异种移植物的H & E染色显示出相似的中分化腺癌细胞特征(
)。帕那替尼治疗后，肿瘤总大小显著减小(
)。Ki-67染色显示，与对照组相比，帕那替尼组肿瘤细胞增殖减少(
、
)。CD31染色显示，与对照组相比，帕那替尼治疗LIV31肿瘤的微血管密度没有显著差异(
、
)。裂解半胱天冬酶-3(CC3)染色和TUNEL染色试验显示，与对照组相比，帕那替尼治疗的肿瘤中细胞凋亡显著增加(
、
)。通过蛋白质印迹和IHC可以证明，帕那替尼降低了FGFR及其下游信号标记FRS2、AKT和ERK的磷酸化(
~
)。逆转录聚合酶链反应显示，用帕那替尼治疗后，FGFR-CCDC6融合体的表达持续存在(
)。
2.3. 帕那替尼与吉西他滨和顺铂联合用药没有协同作用
顺铂(2.5 mg/ (kg·周)腹腔注射)联合吉西他滨(50 mg/ (kg·周)腹腔注射)治疗的标准方案显著抑制肿瘤生长(
P
< 0.0001)，且明显比单独使用帕那替尼更有效(
P
< 0.0001，
、
)。然而，帕那替尼与吉西他滨和顺铂的联合并不比吉西他滨和顺铂的联合更有效(
P
=0.7)。帕那替尼在体内对胆管癌有抗癌作用，但与吉西他滨和顺铂联合给药时没有附加或协同作用。单独用帕那替尼，单用吉西他滨和顺铂，及联合帕那替尼与吉西他滨和顺铂治疗的小鼠的体质量与用赋形剂治疗的小鼠的体重没有差异(
)。Ki-67染色显示吉西他滨和顺铂治疗后肿瘤细胞增殖减少(
、
)。当用吉西他滨和顺铂治疗时，胆管癌肿瘤的微血管密度没有降低。CC3染色和TUNEL分析显示，与对照组相比，吉西他滨和顺铂联合治疗的肿瘤具有显著的凋亡活性(
、
)。用吉西他滨和顺铂治疗没有降低FGFR或下游信号分子FRS2、AKT和ERK的磷酸化(
~
)。用吉西他滨和顺铂治疗后，通过非定量RT-PCR评估，FGFR-CCDC6融合体的表达持续存在(
)。
3. 讨论
FGFR融合物已被确定为多种癌症的一种新的、药物化的共基因靶点，包括膀胱癌(FGFR3)
[
18
]
、胶质母细胞瘤(FGFR1和FGFR3)
[
17
]
、乳腺癌(FGFR2)
[
8
]
和最近的CCA(FGFR2)。胆管癌和其他癌症中发现了FGFR2与多个配偶体的基因融合，这些配偶体提供促进寡聚化的二聚化结构域，导致FGFR激酶和多种下游信号通路的组成型激活，包括RAS/MASK和PI3K/AKT通路
[
7
,
19
]
。因此，FGFR2的小分子抑制剂可作为该患者群体的合理疗法。在当前的研究中，我们建立并验证了一种新的iCCA PDX模型，LIV31，其内源性表达FGFR2-CCD6融合蛋白。这种融合基因及表达产物随后在RT-PCR、桑格测序、G显带等一系列方法中得到了验证。研究人员在一名乳腺癌患者中发现了FGFR2与CCDC6的融合基因
[
8
]
。包括FGFR-CCDC6融合在内的FGFR融合蛋白的过表达激活细胞外信号调节激酶信号传导，并在体外诱导细胞增殖
[
8
]
，这说明我们的发现并不是偶然的。FGFR抑制剂帕那替尼在FGFR活性失调的多种人类肿瘤中显示了有效的抗肿瘤活性
[
17
,
20
-
22
]
。值得注意的是，与它们的亲本细胞相比，经工程改造过表达FGFR1-4的细胞对帕那替尼显示出更高的敏感性
[
20
,
22
]
。对于携带FGFR2融合蛋白的晚期iCCA患者，帕那替尼可诱导肿瘤缩小，这包括一例之前对帕唑替尼有反应并随后进展的患者
[
10
]
。帕唑替尼优先靶向血管内皮生长因子受体和血小板衍生生长因子受体，但对FGFR也有适度的疗效。因此，我们在这种FGFR2-CCD6驱动的iCCA小鼠模型中检测了帕那替尼的抗肿瘤作用。在20 mg/kg时，帕那替尼显著抑制LIV31胆管癌模型的肿瘤生长，与赋形剂组相比，帕那替尼组同期肿瘤体积明显减小，且存活曲线显示肿瘤体积小于400 mm
3
的小鼠的百分比明显提高。此外，免疫组化和蛋白质印迹显示帕那替尼抑制FGFR信号的激活，导致LIV31胆管癌肿瘤中细胞增殖的抑制和凋亡的诱导。该模型中帕那替尼的效力类似于先前在FGFR扩增或突变肿瘤和BCR ABL驱动肿瘤模型中观察到的效力
[
17
,
23
]
。这说明了FGFR2抑制剂帕那替尼对iCCA肿瘤的抑制作用。吉西他滨和顺铂是晚期胆管癌的标准化疗组合，仅达到26.1%的有效率，并将总生存期中位数从8.1月延长至11.7月
[
5
]
。因此，研究FGFR抑制剂是否能增强吉西他滨和顺铂在含FGFR2融合的胆管癌中的抗癌作用是非常重要的。在本次实验中，我们将单独使用FGFR2抑制剂帕那替尼、单用吉西他滨和顺铂，以及FGFR2抑制剂帕那替尼联合吉西他滨和顺铂的标准化疗组合做了对比，结果发现，在给定给药剂量下，单用标准化疗方案明显比单独使用帕那替尼更有效，而二者联用时，帕那替尼并没有增强这种联合治疗的效果。帕那替尼与吉西他滨和顺铂缺乏协同作用可能是因为我们给予了相对高剂量的吉西他滨和顺铂；或者，可能是由于最近证实的许多酪氨酸激酶抑制剂阻止吉西他滨在癌细胞积累的作用
[
24
]
，这使组合应用的效果更差。由于吉西他滨(50 mg/kg)和顺铂(2.5 mg/kg)的组合几乎完全抑制肿瘤生长，因此很难通过与帕那替尼的组合达到额外的效果。因此，下一步可能需要研究FGFR抑制剂和低剂量吉西他滨和顺铂联合治疗的体内效果，包括在使用FGFR抑制剂之前使用吉西他滨序贯给药的研究。信号通路方面，单用帕那替尼对FGFR及其下游信号标记FRS2、AKT和ERK的磷酸化均有明显的抑制作用，而相比之下，标准化疗方案则未见有明显的通路抑制表现，这正是靶向治疗的优势所在，从另一方面而言，FGFR融合基因及其表达产物有可能作为FGFR抑制剂有效性的预测性生物标志物。基质金属蛋白酶可促进肿瘤细胞的增殖和转移，在FGFs和FGFR的某些复合物中被发现与信号转导有关
[
25
-
28
]
。因此我们比较了应用FGFR2抑制剂时MMP在通路中的影响，实验结果显示，在用FGFR2抑制剂治疗后，MMP2、MMP3和MMP9的表达没有显著变化，表明这些基质金属蛋白酶不是FGFR2抑制剂帕那替尼抑制肿瘤发生作用的直接介质。目前一线联合化疗虽然有所进展，但是治疗选择仍然有限，因为没有标准的二线治疗方案。针对EGFR、VEGF和MEK单独或与化疗联合的靶向治疗已在胆管癌进行实验
[
29
]
。然而，现有的临床试验数据并不支持它们在胆管癌中的应用。帕唑帕尼，是一种针对VEGFR、PDGFR和FGFR的多靶点TKI药物。最近其已被报道可诱导在一线联合化疗后进展的FGFR2-TACC3融合的晚期胆管癌患者肿瘤的缩小
[
10
]
。因此，FGFR抑制剂可用作治疗FGFR遗传改变的胆管癌的二线疗法，特别是存在FGFR2融合的病例。
总之，我们报道了一种新的胆管癌PDX模型，该模型表达FGFR 2-CCD6融合蛋白，在肯定一线化疗的作用基础上证明了非特异性多激酶抑制剂帕那替尼对该肿瘤的临床前抗肿瘤活性。在这个PDX模型上，帕那替尼似乎与标准化疗吉西他滨和顺铂没有相加或协同作用。但与对照组相比之下，单独应用帕那替尼对PDX模型的抑制作用还是显而易见的。
Funding Statement
广东省自然科学基金(2018A030313659)
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