本帖最后由 橙子KARS突变 于 2016-6-26 20:00 编辑
A combinatorial strategy for treating KRAS-mutant lung cancer
Eusebio Manchado,
Susann Weissmueller,
John P. Morris,
Chi-Chao Chen,
Ramona Wullenkord,
Amaia Lujambio,
Elisa de Stanchina,
John T. Poirier,
Justin F. Gainor,
Ryan B. Corcoran,
Jeffrey A. Engelman,
Charles M. Rudin,
Neal Rosen
& Scott W. Lowe
Affiliations
Contributions
Corresponding authors
Nature (2016) doi:10.1038/nature18600 Received23 November 2015Accepted24 May 2016Published online22 June 2016
Therapeutic targeting of KRAS-mutant lung adenocarcinoma represents a major goal of clinical oncology.
具有KRAS突变的肺腺癌的靶向治疗是临床肿瘤治疗中的一个主要目标。
KRAS itself has proved difficult to inhibit, and the effectiveness of agents that target key KRAS effectors has been thwarted by activation of compensatory or parallel pathways that limit their efficacy as single agents.
已经证明KRAS自身很难被抑制，而因为代偿激活或者旁路激活，靶向KRAS关键效应器（effectors）药物的有效性受到阻碍，从而限制了其作为单药的效果。
Here we take a systematic approach towards identifying combination targets for trametinib, a MEK inhibitor approved by the US Food and Drug Administration, which acts downstream of KRAS to suppress signalling through the mitogen-activated protein kinase (MAPK) cascade.
因此我们提出了一个系统方案，联合trametinib，一款被US FDA批准的MEK抑制剂，通过抑制MAPK级联途径来作用KRAS的下游通路。
Informed by a short-hairpin RNA screen, we show that trametinib provokes a compensatory response involving the fibroblast growth factor receptor 1 (FGFR1) that leads to signalling rebound and adaptive drug resistance.
通过小发夹RNA筛选，显示trametinib激活了涉及FGFR1的互补响应，其导致了信号通路的重建和适应性耐药。
As a consequence, genetic or pharmacological inhibition of FGFR1 in combination with trametinib enhances tumour cell deathin vitro and in vivo.
因此，体内和体外实验都显示，对FGFR1的基因或者药理学上的抑制，联合trametinib，能够增强肿瘤细胞的死亡。
This compensatory response shows distinct specificities:
该互补响应显示了一些不同的特性：
it is dominated by FGFR1 in KRAS-mutant lung and pancreatic cancer cells, but is not activated or involves other mechanisms in KRAS wild-type lung and KRAS-mutant colon cancer cells.
在KRAS突变的肺癌和前列腺癌中，（该响应）主要由FGFR1控制。但并未在KRAS野生型肺癌和KRAS突变的结直肠癌细胞中被激活或涉及到其他作用机制。
Importantly, KRAS-mutant lung cancer cells and patients’ tumours treated with trametinib show an increase in FRS2 phosphorylation, a biomarker of FGFR activation;
重要的是，由trametinib治疗的KRAS突变的肺癌细胞和患者肿瘤显示了增加的FRS2磷酸化，这是FGFR激活的生物标识。
this increase is abolished by FGFR1 inhibition and correlates with sensitivity to trametinib and FGFR inhibitor combinations.
FRS2磷酸化的增加可由对FGFR1的抑制而抵消，并且其与trametinib和FGFR抑制剂联合的敏感性正相关。
These results demonstrate that FGFR1 can mediate adaptive resistance to trametinib and validate a combinatorial approach for treating KRAS-mutant lung cancer.
这些结果显示FGFR1可介导对trametinib的适应性抵抗，并且验证了该联合方案对治疗KRAS突变的肺癌的效果。
http://www.nature.com/nature/journal/vaop/ncurrent/full/nature18600.html
Abemaciclib data highlight Eli Lilly’s case on CDK 4/6
Can Eli Lilly’s ($LLY) CDK 4/6 inhibitor abemaciclib still make a splash after Pfizer ($PFE) grabbed the pioneering OK in the field for palbociclib (Ibrance) and Novartis ($NVS) has touted a promising early end to their pivotal study for ribociclib?
The next big turning point on that front is looming as analysts look to see if Lilly can wrap its key franchise trial early as well. But a new Phase I study covering a range of cancers and published in Cancer Discovery underscores some of the reasons the FDA decided to hand out “breakthrough” status on abemaciclib. And it also highlights reasons why this drug still has potential to differentiate itself and vault ahead of its major league rivals.
CDK 4/6 inhibitors like abemaciclib are designed to block a key pathway in cell proliferation that runs amok when cancer takes root. Block that process early enough, and a drug can arrest a whole cascade of events that help drive cancer.
The key takeaways from the Lilly study: Unlike the two rivals, which are typically dosed three weeks on and one week off to manage the dose-limiting toxicity of neutropenia for their drugs, abemaciclib’s red flag is for severe fatigue, allowing for continual dosing. Prominent researchers in the study also highlight that Lilly’s drug apparently hits CDK 4 harder than 6, possibly sparing white blood cells. This may help explain why their drug has been able to score more significant data as a monotherapy than the rivals, which are provided as a combo with hormonal therapy.
“For the other two agents (palbociclib and ribociclib), the (single agent) response rates are low with these drugs,” says Dana Farber investigator Geoffrey Shapiro, who’s done work on all three big CDK 4/6 inhibitors.
“We have a fairly hefty response rate for hormone receptor-positive cancer. That’s a bit of a difference,” he adds, and perhaps a key reason why the FDA handed out the breakthrough title, which is intended to help facilitate the development process.
To be sure, says Shapiro, much of what they’re still learning about abemaciclib is preliminary. Hammering away at CDK 4/6 continuously may improve efficacy, he notes, but it may also turn out that constant inhibition may actually encourage resistance, forcing the cancer to find a new pathway. On/off dosing might be able to avoid that, but a lot more work needs to be done before that point can be determined.
Researchers recruited 225 patients for this study. In the expansion phase, abemaciclib was administered as a single agent to 47 patients with breast cancer, 68 with non-small cell lung cancer, 17 with glioblastoma, 26 with melanoma and 15 with colorectal cancer.
Lilly was looking for a better idea of which patients would be most likely to respond and uncovered several key signs for hormone-receptor positive breast cancer and KRAS-mutant NSCLC.
Out of the 36 hormone receptor-positive breast cancer cases, 11 had a partial response while 18 patients had stable disease. Among 68 patients with NSCLC, there were only two partial responses and 31 cases of stable disease. Significantly, one of the partial responses and 12 instances of stable disease involved KRAS-mutant NSCLC.
In breast cancer, the median PFS for the entire population was 5.8 months, Shapiro reports. The median PFS for the hormone receptor-positive population was 8.8 months.
“All breast cancer patients who achieved RECIST response (The Response Evaluation Criteria In Solid Tumors for judging a response) were hormone-receptor positive. Among these patients, the median duration of response was 13.4 months.
In lung cancer: Among patients with tumors harboring KRAS mutation, 9 out of the 29 had a PFS rate greater than 24 weeks (6 months). “Among patients with KRAS wild type tumors, 4/33 had PFS > 24 weeks (6 months). Also, of 4 patients who received abemaciclib > 12 months, 3 had tumor harboring KRAS mutation.
“It is noteworthy that KRAS mutated lung cancer is subdivided into KRAS alone,” noted Shapiro, “KRAS with concomitant TP53 mutation and KRAS with concomitant LKB1 (STK11) loss. KRAS/LKB1 predicts an especially aggressive phenotype. Tumor regressions were noted across these subdivisions of KRAS mutant lung cancer.
“So, although more work needs to be done to truly identify the lung cancer population most likely to benefit from abemaciclib monotherapy, these data in KRAS mutant disease are very promising.
“Finally, for your question about ‘what did we learn, or ‘what was surprising or confirmed,’” adds Shapiro, “it is noteworthy that we confirmed preclinical models indicating abemaciclib can cross the blood brain barrier. Among glioblastoma patients, cerebrospinal fluid concentrations approximated those in plasma, and 2 glioblastoma patients have achieved very long term benefit on abemaciclib.”
Provided the data hold up in the first pivotal study, an approval for Eli Lilly is almost assured. The FDA understands this mechanism well, has been working with three big players that have devoted significant resources to the trials and gave breakthrough status to Pfizer and Lilly to help hurry things along.
Whether Lilly can make the big jump to top contender for this blockbuster market, though, remains to be seen. And Pfizer’s investigators haven’t hesitated to counter that abemaciclib could have severe gastrointestinal issues.
With billions at stake, all the stops are being pulled out.
http://www.fiercebiotech.com/abemaciclib-data-highlight-eli-lilly-s-case-for-vaulting-ahead-cdk-4-6
内容很全面啊，谢谢分享
yybhkgy 发表于 2016-1-22 10:59
申请加群了，偶也是KRAS突变者，也是egrh21突变者，很难共存的类型。在寻找防止耐药的可能与大概率，一直在 ...
会不会其中一种是假阳性？
谢谢分享，学习参考:)
JAMA：MEK抑制剂对KRAS突变型肺癌治疗无益添新证
KRAS突变通过激活下游信号通路包括丝裂原活化蛋白激酶（MAPK）通路含MAPK激酶（MEK），导致肿瘤发展和生长。
近期，一项发表在JAMA杂志上的新研究提示，对之前已治疗的晚期KRAS突变非小细胞肺癌（NSCLC）患者来说，与单独应用多西他赛比较，selumetinib联合多西他赛未能提供任何显著获益。
研究员Pasi A.Jänne教授（波士顿Dana-Farber癌症研究所）指出，KRAS突变型肺癌在驱动基因亚型中所占的比重最大，但至今无有效的靶向治疗。
背景
Selumetinib是一种口服、强效、选择性MEK抑制剂，理论上可通过调控Ras-Raf-MEK-ERK通路中关键蛋白激酶MEK水平来抑制KARS突变型肿瘤的生长。
之前一项随机II期研究提示，在87例KRAS-突变晚期NSCLC患者中，selumetinib联合多西他赛作为二线治疗方案，可以显著改善患者的中位无进展生存期（PFS）、客观缓解率（ORR）和总生存期（OS）。
这些令人鼓舞的结果促使了III期selumetinib联合治疗评估（SELECT-1）试验的开展。
主要研究
SELECT-1试验一项多中心、随机III期试验，包括510例患者，中位年龄61.4岁。
其中，251例患者接受selumetinib联合多西他赛，254例患者接受安慰剂联合多西他赛。
主要结果
结果显示，在这两个治疗组中，中位PFS和OS并无显著差异。
中位PFS在selumetinib+多西他赛组是3.9个月，安慰剂+多西他赛组为2.8个月。
Selumetinib+多西他赛组的中位OS是8.7个月，安慰剂+多西他赛组的OS是7.9个月。
Selumetinib+多西他赛组和单独多西他赛组的客观缓解率分别为20.1%和13.7%。
两种药物联合方案的中位缓解持续时间是2.9个月，单独多西他赛的中位缓解持续时间为4.5个月。
与单纯多西他赛（45%）相比较，≥3级的不良事件在selumetinib+多西他赛组较为频繁（67%）。
研究人员解释说，与II期试验相比较，在这项研究中接受安慰剂+多西他赛的患者表现更好，可能是由于SELECT-1试验的所有患者被提供预防性G-CSF管理。对这类患者人群而言，这种做法不属于多西他赛单药治疗常规临床实践。
评论
在一份随刊社论中，Jacob Kaufman教授和Thomas E.Stinchcombe教授（美国杜克大学）指出，早些时候的II期试验和目前的这项III期试验的结果差异可能是临床获益仅发生在某些表现良好遗传或信号环境的肿瘤子集中。而且，其他突变的存在或者各种信号通路的相对活性也可能影响对MEK抑制剂的响应。
MEK抑制剂在这种肿瘤亚型中可能是一种可行的策略，但是其他候选药物可能比selumetinib更有效。再或者，MEK抑制剂联合其他靶向治疗可能比联合多西他赛观察到更多的协同效应。
评论专家补充道，靶向治疗的发展对KRAS-突变型NSCLC患者的未来管理至关重要，而且为其他携带KRAS突变的实体恶性肿瘤提供了一种可能的治疗途径。
司美替尼+多西他赛 对比 安慰剂+多西他赛 三期临床结果亚组分析
司美替尼+多西他赛 vs 安慰剂+多西他赛：中位无进展生存期3.9个月 vs 2.8个月 （显著性P=0.44 没有统计学意义）；中位总生存期8.7个月 vs 7.9个月（显著性P=0.64 没有统计学意义）；客观缓解率20.1% vs 13.7%（显著性P=0.05 有统计学意义）；中位缓解时间2.9个月 vs 4.5个月；三级以上不良反应率67% vs 45%. 结论：在既往接受一线治疗进展的KRAS突变非小细胞肺癌患者中，使用司美替尼+多西他赛相对于多西他赛单药并没有改善无进展生存。
亚组分析eFigure1,eFigure2,里面没有任何差别是统计学显著的。只有Q61突变在无进展生存上有获益倾向。最后讨论中堤到其他文献显示：有效率可能与不同突变分型有关：kras单独，kras+p53, kras+stk11。其中伴stk11或p53可能无效。另外kras患者可能对pd-1有效率高。编辑社论提到，本篇结果不排除其他mek抑制剂如GDC-0623由于抑制反馈可能比6244有效率高。联合抑制pi3k/mtor/AKT通路 以及 KRAS G12C直接抑制 是可能的尝试方向。
谢谢橙子。
人需要有点钻研精神