晚期NSCLC靶向和化疗方案选择的几个问题

这个XL647没办法对付T790，一线效率又不如易，特，所以就无下文了。

老马 发表于 2013-6-27 11:01

                               
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这个XL647没办法对付T790，一线效率又不如易，特，所以就无下文了。

凡德效率也远不如易特，但是可以拿来轮换， XL647用来做轮换是否一样可行？又多种武器。

Differential Sensitivity of ERBB2 Kinase Domain Mutations towards Lapatinib
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3203921/
Lapatinib-resistant ERBB2 mutations were found to be highly resistant towards AEE788 treatment but remained sensitive towards the dual irreversible inhibitors CL-387785 and WZ-4002.
Differential Sensitivity of ERBB2 Kinase Domain Mutations towards Lapatinib.pdf (1.56 MB, 下载次数: 161)

2013-7-3 12:08 上传

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Clin Cancer Res. 2013 May 1;19(9):2584-91. doi: 10.1158/1078-0432.CCR-12-3173. Epub 2013 Mar 20.
Characteristics of lung cancers harboring NRAS mutations.
Ohashi K, Sequist LV, Arcila ME, Lovly CM, Chen X, Rudin CM, Moran T, Camidge DR, Vnencak-Jones CL, Berry L, Pan Y, Sasaki H, Engelman JA, Garon EB, Dubinett SM, Franklin WA, Riely GJ, Sos ML, Kris MG, Dias-Santagata D, Ladanyi M, Bunn PA Jr, Pao W.
SourceVanderbilt-Ingram Cancer Center, Department of Medicine/Division of Hematology-Oncology, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA.

Abstract
PURPOSE: We sought to determine the frequency and clinical characteristics of patients with lung cancer harboring NRAS mutations. We used preclinical models to identify targeted therapies likely to be of benefit against NRAS-mutant lung cancer cells.

EXPERIMENTAL DESIGN: We reviewed clinical data from patients whose lung cancers were identified at six institutions or reported in the Catalogue of Somatic Mutations in Cancer (COSMIC) to harbor NRAS mutations. Six NRAS-mutant cell lines were screened for sensitivity against inhibitors of multiple kinases (i.e., EGFR, ALK, MET, IGF-1R, BRAF, PI3K, and MEK).

RESULTS: Among 4,562 patients with lung cancers tested, NRAS mutations were present in 30 (0.7%; 95% confidence interval, 0.45%-0.94%); 28 of these had no other driver mutations. 83% had adenocarcinoma histology with no significant differences in gender. While 95% of patients were former or current smokers, smoking-related G:C>T:A transversions were significantly less frequent in NRAS-mutated lung tumors than KRAS-mutant non-small cell lung cancer [NSCLC; NRAS: 13% (4/30), KRAS: 66% (1772/2733), P < 0.00000001]. Five of 6 NRAS-mutant cell lines were sensitive to the MEK inhibitors, selumetinib and trametinib, but not to other inhibitors tested.

CONCLUSION: NRAS mutations define a distinct subset of lung cancers (&#8764;1%) with potential sensitivity to MEK inhibitors. Although NRAS mutations are more common in current/former smokers, the types of mutations are not those classically associated with smoking.

&copy;2013 AACR.
http://www.ncbi.nlm.nih.gov/pubmed/23515407?dopt=Abstract

Genetic Variation in East Asians Found to Explain Resistance to Cancer Drugs
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Published: Mar. 18, 2012
Updated: Mar. 18, 2012
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By Duke Medicine News and Communications

A multinational research team led by scientists at Duke-NUS Graduate Medical School has identified the reason why some patients fail to respond to some of the most successful cancer drugs.

Tyrosine kinase inhibitor drugs (TKI) work effectively in most patients to fight certain blood cell cancers, such as chronic myelogenous leukemia (CML), and non-small-cell lung cancers (NSCLC) with mutations in the EGFR gene.

These precisely targeted drugs shut down molecular pathways that keep these cancers flourishing and include TKIs for treating CML, and the form of NSCLC with EGFR genetic mutations.

Now the team at Duke-NUS Graduate Medical School in Singapore, working with the Genome Institute of Singapore (GIS), Singapore General Hospital, and the National Cancer Centre Singapore, has discovered that there is a common variation in the BIM gene in people of East Asian descent that contributes to some patients' failure to benefit from these tyrosine kinase inhibitor drugs.

"Because we could determine in cells how the BIM gene variant caused TKI resistance, we were able to devise a strategy to overcome it," said S. Tiong Ong, MBBCh, senior author of the study and associate professor in the Cancer and Stem Cell Biology Signature Research Programme at Duke-NUS and Division of Medical Oncology, Department of Medicine, at Duke University Medical Center.

"A novel class of drugs called the BH3-mimetics provided the answer," Ong said. "When the BH3 drugs were added to the TKI therapy in experiments conducted on cancer cells with the BIM gene variant, we were able to overcome the resistance conferred by the gene. Our next step will be to bring this to clinical trials with patients."

Said Yijun Ruan, PhD, a co-senior author of this study and associate director for Genome Technology and Biology at GIS: "We used a genome-wide sequencing approach to specifically look for structural changes in the DNA of patient samples. This helped in the discovery of the East Asian BIM gene variant. What's more gratifying is that this collaboration validates the use of basic genomic technology to make clinically important discoveries."

The study was published online in Nature Medicine on March 18.

If the drug combination does override TKI resistance in people, this will be good news for those with the BIM gene variant, which occurs in about 15 percent of the typical East Asian population. By contrast, no people of European or African ancestry were found to have this gene variant.

"While it's interesting to learn about this ethnic difference for the mutation, the greater significance of the finding is that the same principle may apply for other populations," said Patrick Casey, PhD, senior vice dean for research at Duke-NUS and James B. Duke Professor of Pharmacology and Cancer Biology.

"There may well be other, yet to be discovered gene variations that account for drug resistance in different world populations. These findings underscore the importance of learning all we can about cancer pathways, mutations, and treatments that work for different types of individuals. This is how we can personalize cancer treatment and, ultimately, control cancer."

"We estimate that about 14,000 newly diagnosed East Asian CML and EGFR non-small-cell lung cancer patients per year will carry the gene variant," Ong said. "Notably, EGFR NSCLC is much more common in East Asia, and accounts for about 50 percent of all non-small-cell lung cancers in East Asia, compared to only 10 percent in the West."

The researchers found that drug resistance occurred because of impaired production of BH3-containing forms of the BIM protein. They confirmed that restoring BIM gene function with the BH3 drugs worked to overcome TKI resistance in both types of cancer.

"BH3-mimetic drugs are already being studied in clinical trials in combination with chemotherapy, and we are hopeful that BH3 drugs in combination with TKIs can actually overcome this form of TKI resistance in patients with CML and EGFR non-small-cell lung cancer," Ong said. "We are working closely with GIS and the commercialization arm of the Agency for Science, Technology & Research (A*STAR), to develop a clinical test for the BIM gene variant, so that we can take our discovery quickly to the patient."

The major contributors to the study include additional researchers and teams from the Duke-NUS Graduate Medical School, Genome Institute of Singapore (Dr. Yijun Ruan and Dr. Axel Hillmer), Singapore General Hospital (Dr. Charles Chuah), and National Cancer Centre Singapore (Dr. Darren Wan-Teck Lim).

In addition, the investigators also received important contributions from Akita University Graduate School of Medicine, Japan (Dr. Naoto Takahashi), the Cancer Science Institute of Singapore (Dr. Ross Soo), the National University Cancer Institute of Singapore (Drs. Liang Piu Koh and Tan Min Chin), the Yong Loo Lin School of Medicine, National University of Singapore (Dr. Seet Ju Ee), the University of Bonn, Germany (Dr. Markus N&ouml;then), the University of Malaya (Dr. Veera Nadarajan), and the University of Tokyo, Japan (Dr. Hiroyuki Mano).

The study was supported by grants from the National Medical Research Council (NMRC) of Singapore; Biomedical Research Council (BMRC) of A*STAR, Singapore; Genome Institute of Singapore; Singapore General Hospital; and two NMRC Clinician Scientist Awards to Dr. Ong and Dr Chuah.

Nat Med：BIM基因变异可能是东亚人对TKI耐受原因来源
3月18日，国际著名杂志《自然—医学》Nature Medicine在线刊登了杜克-新加坡大学医学院的科学家领导的一个国际研究小组的最新研究成果“A common BIM deletion polymorphism mediates intrinsic resistance and inferior responses to tyrosine kinase inhibitors in cancer，”，文章中，研究者找到了对大部分人有效的一类抗癌药物，却对某些患者无效的原因。

酪氨酸激酶抑制剂（TKIs）可在大部分慢性髓细胞性白血病（CML）患者和EGFR基因突变的非小细胞肺癌（NSCLC）患者体内发挥有效抗癌效应。这些精确靶向性药物可以关闭对癌症旺盛生长起重要作用的分子信号通路。

在新研究中，来自杜克-新加坡大学医学院、新加坡基因组研究院（GIS）、新加坡中央医院和新加坡国立癌症中心的研究人员共同协作，发现东亚血统人群共有的一种BIM基因变异导致了某些患者无法受益于这些酪氨酸激酶抑制剂药物。

“因为我们确定了细胞内BIM基因变异导致TKI耐受的机制，因此基于此发现我们设计出克服它的策略，”文章的资深作者、杜克大学医学中心医学系医学肿瘤学部、杜克-新加坡大学医学院癌症和干细胞生物学标记研究项目副教授S. Tiong Ong，说。

Ong 说：“一类新型的药物称之为BH3拟药（BH3-mimetics）提供了答案。当我们在实验中将BH3药物添加到TKI治疗中作用于带有BIM基因变异的癌细胞时，我们能够克服BIM基因导致的耐药。下一步我们将在临床试验中验证这一结果。”

新加坡基因组研究院基因组技术和生物学副主任、文章的共同资深作者阮一骏（Yijun Ruan）说：“我们利用全基因组测序技术特异地筛查了患者样品DNA的结构改变，帮助我们发现了东亚人BIM基因变异。更为重要的是，这项协作确证了可利用基础基因组技术来获得临床重要研究发现。”

如果联合用药能够克服TKI耐药，这对于携带BIM基因变异的患者而言无疑是个极好的消息，因为在大约15%的东亚人群中均有这种变异。与之形成鲜明对比的是，欧洲或非洲血统的人们未发现有这种基因变异。

杜克-新加坡大学医学院资深副院长、药理学和癌症生物学教授Patrick Casey 博士说：“虽然很感兴趣想了解该突变的这种人种差异，然而这些研究发现更重要的意义在于相同的原理有可能适用于其他人群。有可能世界上其他的不同人群也因为某些其他的基因变异导致了药物耐受。这些研究成果强调了解不同个体类型癌症信号、突变和治疗作用机制的重要性。我们必须通过如此才能发展个体化癌症治疗，最终控制肿瘤。”

Ong说：“我们估计每年约有1.4万的新确诊东亚CML和EGFR非小细胞肺癌患者携带这种基因变异。值得注意的是，EGFR非小细胞肺癌在东亚非常常见，约占东亚人群非小细胞肺癌患者的50%，远远高于西方的10%。”

研究人员发现药物耐受主要是因为包含BHI3的BIM蛋白生成受损。他们证实用BH3药物修复BIM基因功能就可能克服两种癌症类型的TKI耐受。

Ong 说：“目前已在临床试验中开展BH2拟药联合化疗研究，我们希望将BH3药物与TKI联合使用能够确实帮助CML和EGF非小细胞肺癌患者克服这种TKI耐受。我们正与新加坡基因组研究院和A*STAR展开合作，开发BIM基因变异临床测试，以推动快速筛查这类患者。”

证据提示为防止发生TKI耐药性和克服BIM-多态性-伴TKI耐药性，BH3-模拟药物，例如ABT737，可能被引入NSCLC的治疗或在诊断时或在出现耐药性时。

太全面了，受益匪浅，感谢老马的辛苦劳动，感谢老马为迷茫的癌症患者及家属指点迷津！

关于酪氨酸激酶抑制剂原发性和获得性耐药的EGFR突变的日本肺癌人群中肝细胞生长因子表达的研究
Hepatocyte Growth Factor Expression in EGFR Mutant Lung Cancer with Intrinsic and Acquired Resistance to Tyrosine Kinase Inhibitors in a Japanese Cohort
中文关键词:  表皮生长因子受体-酪氨酸激酶抑制剂（EGFR-TKI），EGFR突变，肝细胞生长因子（HGF），获得性耐药，原发性耐药
英文关键词:EGFR-TKI, EGFR mutation, HGF, Acquired resistance, Intrinsic resistance.
Seiji Yano, Tadaaki Yamada, Shinji Takeuchi, Keisei Tachibana, Yuko Minami, Yasushi Yatabe, Tetsuya Mitsudomi, Hidenori Tanaka, Tatsuo Kimura, Shinzoh Kudoh, Hiroshi Nokihara, Yuichiro Ohe, Jun Yokota, Hidetaka Uramoto, Kosei Yasumoto, Katsuyuki Kiura
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中文摘要:
      引言: 本研究旨在检测EGFR突变肺癌患者中表皮生长因子受体(EGFR)酪氨酸激酶抑制剂(TKI)治疗原发性和获得性耐药相关因子（如: 肝细胞生长因子（HGF）高表达、EGFR T790M继发突变及MET基因扩增）的发生率。方法: 对来自日本11个机构的93例EGFR突变的肺癌患者的97份样本（23份样本来自20例获得性耐药患者、45份样本来自44例原发性耐药[治疗无效]患者、29份样本来自29例治疗敏感患者）进行分析。对HGF表达、EGFR T790M继发突变和MET 基因扩增分别用免疫组织化学、cycleave实时聚合酶链反应（PCR）和荧光原位杂交的方法进行检测。结果: HGF高表达、EGFR T790M继发突变和MET基因扩增在获得性耐药的肺癌患者的发生率分别为61％、52％和9％。在原发性耐药（治疗无效）的肺癌患者，HGF高表达的发生率为29%，而EGFR T790M继发突变和MET基因扩增的发生率分别为0％和4％。与治疗敏感患者相比获得性耐药患者的HGF表达显著增高（P<0.001，Student's t检验）。50％的获得性耐药肿瘤患者同时存在有HGF表达和EGFR T790M继发突变及MET基因扩增。结论: 在EGFR-TKI原发性和获得性耐药的EGFR突变的日本肺癌患者中，HGF高表达较EGFR T790M继发突变或MET基因扩增发生率更高。本研究结果提示HGF表达可能与EGFR突变肺癌EGFR-TKI治疗耐药相关。
英文摘要:
      Introduction: This study was performed to determine the incidence rates of resistance factors, i.e., high-level hepatocyte growth factor (HGF) expression, epidermal growth factor receptor (EGFR) T790M secondary mutation, and MET amplification, in tumors with intrinsic and acquired EGFR tyrosine kinase inhibitor (TKI) resistance in EGFR mutant lung cancer. Methods: Ninety-seven specimens from 93 EGFR mutant lung cancer patients (23 tumors with acquired resistance from 20 patients, 45 tumors with intrinsic resistance from 44 patients [nonresponders], 29 sensitive tumors from 29 patients) from 11 institutes in Japan were analyzed. HGF expression, EGFR T790M secondary mutation, and MET amplification were determined by immunohistochemistry, cycleave real-time polymerase chain reaction, and fluorescence in situ hybridization, respectively. Results: High-level HGF expression, EGFR T790M secondary mutation, and MET amplification were detected in 61, 52, and 9% of tumors with acquired resistance, respectively. High-level HGF expression was detected in 29% of tumors with intrinsic resistance (nonresponders), whereas EGFR T790M secondary mutation and MET amplification were detected in 0 and 4%, respectively. HGF expression was significantly higher in tumors with acquired resistance than in sensitive tumors (p=0.001, Student’s t test). Fifty percent of tumors with acquired resistance showed simultaneous HGF expression with EGFR T790M secondary mutation and MET amplification. Conclusions: High-level HGF expression was detected more frequently than EGFR T790M secondary mutation or MET amplification in tumors with intrinsic and acquired EGFR-TKI resistance in EGFR mutant lung cancer in Japanese patients. These observations provide a rationale for targeting HGF in EGFR-TKI resistance in EGFR mutant lung cancer.
Mechanisms of resistance to EGFR TKIs and development of a new generation of dru.pdf (1.55 MB, 下载次数: 158)

2013-8-6 19:25 上传

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Hepatocyte growth factor expression in EGFR mutant lung cancer with intrinsic an.pdf (1006.09 KB, 下载次数: 128)

2013-8-7 01:39 上传

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老马 发表于 2013-8-4 01:45

                               
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关于酪氨酸激酶抑制剂原发性和获得性耐药的EGFR突变的日本肺癌人群中肝细胞生长因子表达的研究
Hepatocyte ...

谢谢马哥。现在有什么好药是针对HGF高表达的？ 关注中。