成纤维细胞生长因子受体（FGFR）

                                                              成纤维细胞生长因子受体（FGFR）
1成纤维细胞生长因子（FGF）
   早期研究使用的成纤维细胞生长因子（FGFs）主要来自牛脑和脑垂体的提取液，是大约150 个氨基酸结构的酸性或碱性成纤维细胞生长因子（aFGF：FGF1或bFGF：FGF2）。其后分离的 癌基因产物的细胞增殖因子与上述FGFs结构类似，也被分类在FGFs家族，并依次命名为FGF3 ~9。目前已发现23种 FGFs。
FGFs作为细胞间信号分子在胚胎发生和分化过程中起重要作用。FGFs 是由约150~200氨基酸组成的多肽，相互之间的氨基酸序列有20%~50%是相同的。其中心区域有大约 120个氨基酸序列存在高度的同源性（30%~70%）。
2成纤维细胞生长因子受体（FGFR）
   FGFs的信号通路：FGFs与存在于细胞表面的FGFRs结合，将信号传递到胞内。FGFRs有4种基因型(FGFR1~4) ，同是一种跨膜蛋白质，主要由3个部分组成：即胞外段、跨膜区和胞内段。胞外段为配体结合区 ，包括2个或3个免疫球蛋白样功能区。根据FGFRs选择性拼接的差异，目前已知存在7种受体蛋白的亚型结构。如FGFR1有FGFR1b,1c,2b,2c,3b,3c,4 7种， 各自均有不同的配体特异性。同样FGFR2也可产生FGFR2-Ⅲb和FGFR2-Ⅲc两种受体亚型。FGFR2-Ⅲb主要在上皮细胞中表达，FGFR2-Ⅲ c主要在间质细胞中表达。间质细胞表达的FGF7和FGF10能特异性地激活FGFR2- Ⅲb，而FGF2、FGF4、FGF6、FGF8和FGF9则特异性激活FGFR2-Ⅲc，这种结合的 特异性与细胞膜环境和硫酸乙酰肝素有关。其中，FGF10与FGFR2Ⅲb有较高的 亲和力，是特异性配体。当FGFR2胞外段发生点突变(S252W)时，促使FGF7和FGF10激活FGF R2-Ⅲc和FGF2、FGF6、FGF9激活FGFR2-Ⅲb，导致表达这些配体的细胞自分泌信号激活。
　　与多数生长因子受体一样，FGFRs都是酪氨酸激酶型受体，在与配体结合后发生二聚体化，从而激活酪氨酸激酶，在激活Shc/Frs-Raf/MAPKKK-MAPKK-MAPK通路的基础上，通过大量释放磷脂酶C (PLC )、蛋白激酶C(PKC)、磷脂酰肌醇3 -激酶系统(PI3 K)和Ca2+，向细胞内传递信号。
3 FGFR扩增在非小细胞肺癌中的意义
3.1相关文献
（1）中国肺鳞癌成纤维细胞生长因子受体1扩增及临床意义
   FGFR1扩增可能是肺鳞癌潜在分子靶点。本研究纳入177例肺鳞癌患者，分别采用荧光原位杂交和变性高效液性色谱分析方法检测FGFR1拷贝数及EGFR突变。
FGFR1扩增见于24.9%（44/177）的中国肺鳞癌患者，而同期检测肺腺癌患者未见FGFR1扩增（0/89）。与女性(11.8%, 4/34)和不吸烟者(11.8%, 4/34)相比，男性(28.0%, 40/143，p=0.049)和吸烟(28.7%, 39/136，p=0.032)患者FGFR1扩增多见。
组织EGFR突变有多见于FGFR1扩增阴性患者的趋势（p=0.059），而血浆EGFR突变、血浆或组织EGFR突变均表现为与FGFR1扩增不共存（p=0.038，p=0.006）。FGFR1扩增阴性患者血浆EGFR突变概率为21.6%（22/102）,而FGFR1扩增阳性患者血浆EGFR突变概率为5.9%（2/34）；FGFR1扩增阴性患者血浆或组织EGFR突变概率为26.3%（35/133），而FGFR1扩增阳性患者血浆或组织EGFR突变概率仅为6.8%（3/44）。
47例患者接受EGFR-TKI治疗，其中一线17例，二线及二线后30例，接受易瑞沙治疗16例，特罗凯治疗31例，客观有效率4.3%（2/47，2例均为PR）,疾病控制率46.8%（22/47），中位PFS为1.4个月（0.2-24.4月）。FGFR1扩增患者ORR、DCR、PFS及OS分别为0.0%（0/9）、55.6%(5/9)、4.7月、17.1月，而扩增阴性患者对应数值分别为5.3%(2/38)、44.7%(17/38)、6.3月、16.9月，差异均无统计学意义(p值分别为1.000、0.715、0.442、0.929)。
17例EGFR突变且接受EGFR-TKI治疗的患者9例表现为原发耐药，其中一例患者存在K-RAS突变，两例存在FGFR1扩增。
结论：FGFR1扩增常见于中国肺鳞癌患者，且与EGFR突变不共存。FGFR1扩增与EGFR-TKI疗效、PFS及OS无关，但可能介导部分EGFR突变患者对于TKI的原发耐药。
（2）Rapidly Acquired Resistance to EGFR Tyrosine Kinase Inhibitors in NSCLC Cell Lines through De-Repression of FGFR2 and FGFR3 Expression
http://www.plosone.org/article/i ... ournal.pone.0014117
Abstract
Despite initial and sometimes dramatic responses of specific NSCLC tumors to EGFR TKIs, nearly all will develop resistance and relapse. Gene expression analysis of NSCLC cell lines treated with the EGFR TKI, gefitinib, revealed increased levels of FGFR2 and FGFR3 mRNA. Analysis of gefitinib action on a larger panel of NSCLC cell lines verified that FGFR2 and FGFR3 expression is increased at the mRNA and protein level in NSCLC cell lines in which the EGFR is dominant for growth signaling, but not in cell lines where EGFR signaling is absent. A luciferase reporter containing 2.5 kilobases of fgfr2 5′ flanking sequence was activated after gefitinib treatment, indicating transcriptional regulation as a contributing mechanism controlling increased FGFR2 expression. Induction of FGFR2 and FGFR3 protein as well as fgfr2-luc activity was also observed with Erbitux, an EGFR-specific monoclonal antibody. Moreover, inhibitors of c-Src and MEK stimulated fgfr2-luc activity to a similar degree as gefitinib, suggesting that these pathways may mediate EGFR-dependent repression of FGFR2 and FGFR3. Importantly, our studies demonstrate that EGFR TKI-induced FGFR2 and FGFR3 are capable of mediating FGF2 and FGF7 stimulated ERK activation as well as FGF-stimulated transformed growth in the setting of EGFR TKIs. In conclusion, this study highlights EGFR TKI-induced FGFR2 and FGFR3 signaling as a novel and rapid mechanism of acquired resistance to EGFR TKIs and suggests that treatment of NSCLC patients with combinations of EGFR and FGFR specific TKIs may be a strategy to enhance efficacy of single EGFR inhibitors.
（3）


非小细胞肺鳞癌靶向药进展（2012年）.PDF (770.09 KB, 下载次数: 59)

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  Ponatinib is a multikinase inhibitor that was developed to inhibit both native (IC50 0.37 nM) and mutant forms of bcr-abl, including T351I (IC50 2 nM) in patients with chronic myelogenous  leukemia. Preclinical models demonstrate its ability to inhibit growth of FGFR1-amplifed  squamous  cell  lung cancer xenografs as well as greater potency in inhibiting all activated forms of FGFR1-4 compared to dovitinib, brivanib, cediranib and nintedanib. Common  toxicities, reported in the phase II PACE study in CML,  showed rash, myalgia, abdominal pain, headache, arthralgia and thrombocytopenia which refect class-efects of bcr-abl inhibitors. Unusual severe adverse event include pancreatitis.
    BGJ398’s selectivity for FGFR1-3 was demonstrated in vivo by dose-dependent inhibition of bFGF-stimulated angiogenesis but no corresponding impairment of VEGF-induced angiogenesis. Phase I study of this agent is ongoing, with the study design refecting the recognition that rationale-based, biomarker-driven patient enrichment design is ethical  and  feasible even in early clinical development of targeted agents. Tis  phase I study, which started in 12/2009, is limited to patients with tumor that have FGFR1 or FGFR2 amplifcation or FGFR3 mutations. It started enrolling FGFR1-amplifed NSCLC patients in the frst quarter of 2011.

二楼备用。

Ponatinib for Squamous Cell Lung Cancer
http://clinicaltrials.gov/show/NCT01761747
Locations
United States, Massachusetts
Dana-Farber Cancer Institute Recruiting
Boston, Massachusetts, United States, 02215  
Contact: Peter Hammerman, MD, PhD     617-632-6335     phammerman@partners.org      
Principal Investigator: Peter Hammerman, MD, PhD              
Brigham and Women's Hospital Recruiting
Boston, Massachusetts, United States, 02215  
Contact: Peter Hammerman, MD, PhD     617-632-6335     phammerman@partners.org      
Principal Investigator: Peter Hammerman, MD, PhD              
Massachusetts General Hospital Recruiting
Boston, Massachusetts, United States, 02214  
Contact: Rebecca Heist, MD     617-726-1838     rheist@partners.org      
Principal Investigator: Rebecca Heist, MD              
Beth Israel Deaconess Medical Center Recruiting
Boston, Massachusetts, United States, 02215  
Contact: Daniel Costa, MD     617-726-1838     dbcosta@bidmc.harvard.edu      
Principal Investigator: Daniel Costa, MD              

2012年12月14日，美国食品药品监督管理局(FDA)批准Iclusig (ponatinib)治疗有慢性粒性白血病(CML)和Philadelphia染色体阳性急性淋巴母细胞白血病(Ph+ ALL)，两种罕见血和骨髓疾病的成年。
Iclusig正在被批准比处方药用户收费的目标日期2013年3月27日提前超过三个月审评，这个日期监督管理局计划完成药物申请。在监督管理局的优先审评程序下FDA审评Iclusig药物申请，这个程序为当没有满意另外治疗存在，或比上市产品提供显着改善的产品可能提供安全和有效治疗提供提前6个月审评。
Iclusig阻断促进癌细胞发展某些蛋白。药物每天服用1次治疗有CML和Ph+ ALL的慢性，加速，和母细胞相患者其白血病是对一类被称为酪氨酸激酶抑制剂(TKIs)耐药或不能耐受。Iclusig靶向CML细胞有一种特殊突变，被称为T315I，它使这些细胞对当前批准的TKIs耐药。
FDA的药物评价和研究中心血液和肿瘤产品室主任Richard Pazdur，M.D.说：“Iclusig的批准是重要的因为对其他药物不反应的CML患者提供治疗选择，尤其是有T315I 突变很少治疗选择的患者”“Iclusig 是今年底被批准治疗CML的第三个药物和治疗ALL的第二个药物，证实FDA承诺为罕见疾病患者批准安全和有效药物。”
Iclusig在监管局加速批准程序下，该程序提供患者较早得到有前途新药而公司进行另外研究确证药物的获益和安全使用。治疗被赋予孤儿药物指定因为意向治疗一种罕见病或情况。
在449例有各种CML和Ph+ ALL相患者一项单组临床试验评价Iclusig的安全性和有效性。所有参加者用Iclusig治疗。
通过在大多数CML患者发现的表达Philadelphia染色体遗传突变细胞百分率减低，重大细胞遗传学反应(MCyR)证实药物的有效性。所有患者的54%和70%患者有T315I 突变实现MCyR。在分析时尚未达到MCyR的中位时间。
在CML和Ph+ ALL加速和母细胞相，通过经历白细胞计数正常化或无白血病证据(重大血液学反应或MaHR)患者数确定Iclusig的有效性。

结果显示：
●有CML加速相患者52% 经历MaHR中位时间9.5个月；
●有母细胞相CML患者31%实现MaHR中位时间4.7个月； 和
●有Ph+ ALL患者41%实现MaHR中位时间3.2个月。
Iclusig正在被批准有一个黑框警告警告患者和卫生保健专业人员药物可能致血液凝固和肝脏毒性。临床试验期间最常报道副作用包括高血压，皮疹，腹痛，疲乏，头痛，干皮肤，便秘，发热，关节痛，和恶心。
Iclusig是由在麻省剑桥的ARIAD药业上市， Bosulif是由位于纽约城的Pfizer上市，和Synribo是由位于滨州的Frazer， Teva药业上市。Marqibo是由加州旧金山的Talon Therapeutics公司上市。

批准日期：2012年12月14日；改善：Ariad Pharmaceuticals，Inc.

ICLUSIG® (ponatinib)片为口服使用

美国初次批准：2012

一般描述
Iclusig (ponatinib)是一种激酶抑制剂。盐酸ponatinib化学名is 3-(imidazo[1,2-b]pyridazin-3ylethynyl)-4-methyl-N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}benzamide hydrochloride. 分子式是C29H28ClF3N6O相当于分子量569.02 g/mol。其结构如下：

作用机制
Ponatinib是一种激酶抑制剂。Ponatinib在体外抑制ABL和T315I突变体ABL酪氨酸激酶的活性有IC50浓度分别为0.4和2.0 nM。Ponatinib抑制另外的激酶在体外的活性有IC50浓度0.1和20 nM间，包括VEGFR，PDGFR，FGFR，EPH受体和激酶的SRC家族，和KIT，RET，TIE2，和FLT3的成员。Ponatinib在体外抑制表达天然或突变体BCR-ABL，包括T315I细胞的生存能力。在小鼠中，用ponatinib治疗当与对照比较时减低表达天然或T315I突变体BCR-ABL肿瘤的大小。
适应证和用途
Iclusig是一种激酶抑制剂适用于为治疗对既往酪氨酸激酶抑制剂治疗耐药或不能耐受的有慢性相，加速相，或母细胞相慢性粒性白血病(CML)成年患者或对既往酪氨酸激酶抑制剂治疗耐药或不能耐受的Philadelphia染色体阳性急性淋巴母细胞白血病(Ph+ALL)(1)。这个适应证是根据反应率。没有用Iclusig的试验证明改善疾病相关症状或增加生存。

剂量和给药方法
● 45 mg有或无食物口服每天1次 (2)
● 对血液学和非-血液学毒性调整剂量或中断给药 (2.2，2.3)

剂型和规格
片：15 mg和45 mg (3)

禁忌证
无。

警告和注意事项
● 充血性心衰：监视患者充血性心衰的体征和症状和临床有指针时治疗 (5.3，6)。
● 高血压：监视高血压和临床有指针时治疗 (5.4，6)。
● 胰腺炎：每月监视血清酯酶； 中断或终止Iclusig (2.3，5.5，6)。
● 出血：对严重出血中断Iclusig (5.6，6).
● 液体潴留：监视患者for 液体潴留； 中断，reduce，or 终止Iclusig (5.7，6)。
● 心律失常：监视心律失常的症状 (5.8，6)。
● 骨髓抑制：血小板减少，中性粒细胞减少，和贫血可能需要中断或减低剂量。每两周监视全细胞计数共3个月和然后每月和当临床上指示。对ANC < 1000/mm3或血小板减少 < 50,000/ mm3中断Iclusig (2.2，5.9，6)。
● 肿瘤溶解综合征：开始用Iclusig治疗前确保水化和纠正高尿酸水平 (5.10).
● 伤口愈合受到损害和胃肠道穿孔：在接受大型手术患者中短暂中断治疗(5.11)。
● 胚胎-胎儿毒性：可能致胎儿危害。劝告妇女对胎儿的潜在风险(5.12，8.1)。

不良反应
最常见非-血液学不良反应(≥ 20%)是高血压，皮疹，腹痛，疲乏，头痛，干皮肤，便秘，关节痛，恶心，和发热。血液学不良反应包括血小板减少，贫血，中性粒细胞减少，淋巴细胞减少，和白细胞减少(6)。
为报告怀疑不良反应，联系ARIAD Pharmaceuticals，Inc. 电话(1-855-55-ARIAD)或FDA电话1-800-FDA-1088或www.fda.gov/medwatch

药物相互作用
强CYP3A抑制剂：如果共同给药不能避免减低 Iclusig剂量 (7.1)

特殊人群中使用
未曾在小于18岁患者中试验Iclusig的安全性和疗效。(8.4).

靶点那么多，副作用会不会很厉害。

FGFR1扩增常见于中国肺鳞癌患者，且与EGFR突变不共存。

是不是意味着鳞癌中吃易特效果不好的都应该考虑这个？

For clinical trials, when I look through: http://clinicaltrials.gov/ct2/results?term=FGFR&recr=Open I see these current possibilities:
- http://clinicaltrials.gov/ct2/show/NCT01515969 (Tarceva (erlotinib) and Novartis dovitinib (TKI258) for NSCLC)

- http://clinicaltrials.gov/ct2/show/NCT01004224
(Novartis BGJ398)

- http://clinicaltrials.gov/ct2/show/NCT00979134
(AstraZeneca AZD4547)

- http://clinicaltrials.gov/ct2/show/NCT01497392
(Novartis dovitinib lactate (TKI258), gemcitabine hydrochloride, and capecitabine)

There's a couple of others I omitted (Europe-only, Japan-only)
http://clinicaltrials.gov/ct2/show/NCT01283945

For research articles about FGFR and lung cancer
http://www.ncbi.nlm.nih.gov/pubmed?term=FGFR%20lung%20cancer I noticed a few experimental chemicals mentioned, including:

Novartis dovitinib:
I didn't find specific articles on this for lung cancer, but FWIW there are some articles on it. I couldn't tell from these whether it would be likely to be promising for lung cancer or not:
http://www.ncbi.nlm.nih.gov/site ... h&term=dovitini b

Ariad ponatinib (AP24534):
http://www.ncbi.nlm.nih.gov/pubmed/22238366
http://mct.aacrjournals.org/content/11/3/690
http://mct.aacrjournals.org/cont ... 35-7163.MCT-11-0450

Pfizer (Parke-Davis) PD173074:
http://stm.sciencemag.org/content/2/62/62ra93.full
http://www.ncbi.nlm.nih.gov/pubmed/21160078
(and interestingly, even a mention of it for SCLC which I didn't think had any candidate targeted drug yet - http://www.ncbi.nlm.nih.gov/pubmed/19903855)

Eli Lily LY2874455:
http://www.ncbi.nlm.nih.gov/pubmed/21900693

Bayer regorafenib (BAY 73-4506):
http://clincancerres.aacrjournal ... /03/14/1078-0432.CC R-11-1900.short?rss=1

AstraZeneca AZD4547:
http://cancerres.aacrjournals.or ... 25/0008-5472.CAN-11 -3034.short?rss=1

This article looks like it might have some useful info about potential inhibitors, but I don't have access to more than just the abstract:
http://www.ncbi.nlm.nih.gov/pubmed/21959109

Rapidly Acquired Resistance to EGFR Tyrosine Kinase Inhibitors in NSCLC Cell Lines through De-Repression of FGFR2 and FGFR3 Expression
http://www.plosone.org/article/i ... ournal.pone.0014117
Despite initial and sometimes dramatic responses of specific NSCLC tumors to EGFR TKIs, nearly all will develop resistance and relapse. Gene expression analysis of NSCLC cell lines treated with the EGFR TKI, gefitinib, revealed increased levels of FGFR2 and FGFR3 mRNA. Analysis of gefitinib action on a larger panel of NSCLC cell lines verified that FGFR2 and FGFR3 expression is increased at the mRNA and protein level in NSCLC cell lines in which the EGFR is dominant for growth signaling, but not in cell lines where EGFR signaling is absent. A luciferase reporter containing 2.5 kilobases of fgfr2 5′ flanking sequence was activated after gefitinib treatment, indicating transcriptional regulation as a contributing mechanism controlling increased FGFR2 expression. Induction of FGFR2 and FGFR3 protein as well as fgfr2-luc activity was also observed with Erbitux, an EGFR-specific monoclonal antibody. Moreover, inhibitors of c-Src and MEK stimulated fgfr2-luc activity to a similar degree as gefitinib, suggesting that these pathways may mediate EGFR-dependent repression of FGFR2 and FGFR3. Importantly, our studies demonstrate that EGFR TKI-induced FGFR2 and FGFR3 are capable of mediating FGF2 and FGF7 stimulated ERK activation as well as FGF-stimulated transformed growth in the setting of EGFR TKIs. In conclusion, this study highlights EGFR TKI-induced FGFR2 and FGFR3 signaling as a novel and rapid mechanism of acquired resistance to EGFR TKIs and suggests that treatment of NSCLC patients with combinations of EGFR and FGFR specific TKIs may be a strategy to enhance efficacy of single EGFR inhibitors.

Rapidly Acquired Resistance to EGFR Tyrosine Kinase Inhibitors in NSCLC (FGFR2,3).PDF (533.14 KB, 下载次数: 31)

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Clinical and biological evidence suggest that EGFR signaling is only one important signaling pathway in lung cancer. If self-sufficiency in growth is a hallmark of cancer, then additional receptor tyrosine kinases capable of signaling for growth, which render EGFR autocrine signaling redundant, can account for the reduced effectiveness of EGFR TKIs in lung cancer. Multiple studies support the hypothesis that EGFR independent receptor tyrosine kinase signaling pathways are active in EGFR TKI insensitive NSCLC.
临床和生物学证据表明，EGFR是肺癌的唯一重要的信号通路。如果癌症的标志是自我增殖，那么额外的受体酪氨酸激酶表示能够增长的信号，导致表皮生长因子受体分泌冗余信号，降低肺癌的EGFR TKI有效性。多项研究支持这一假说，EGFR独立的受体酪氨酸激酶信号通路活跃在EGFR TKI不敏感的非小细胞肺癌。

学习一下。。。。。。。。

希望出现，但愿老妈还来得及……