关于阿法替尼（Bibw 2992）耐药的一些理论和解决方案

One of the main reasons of resistance to EGFR tyrosine kinase inhibitors (TKIs) is that there are alternative mechanisms for persistent activating EGFR downstream signaling, including both RAS/Erk and PI3K/Akt kinase pathways. Therefore, simultaneous inhibition of both pathways would be necessary to reduce tumor cell survival more effectively. One of the candidate combinations is concurrent use of EGFR-TKIs and statins, which are irreversible inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase and have been used to treat hypercholesterolemia through blocking the mevalonate biosynthesis pathway. Beside the cholesterol lowering effect, statins have been shown to induce apoptosis in several tumor types. It affects the synthesis of other products of the mevalonate pathway such as isoprenoids, which are used as substrates for prenylation. Attachment of isoprenoids to RAS proteins facilitates their anchoring to the cell membrane where they carried out their roles. By interrupting the biosynthesis of mevalonate, statins inhibit activation of RAS and downstream signaling cascades, including the RAF/MEK/ERK and PI3K/AKT, which play critical roles in regulation of cell survival and proliferation. Therefore, it seems to be a promising therapeutic approach overcoming tumor resistance to EGFR-TKIs, which is associated with RAS activation.

According to the recent clinical result of phase II trial, a randomized phase II study of gefitinib with or without simvastatin in previously treated patients with advanced NSCLC conducted by Han et al.37 gefitinib plus simvastatin combination produced higher response rates than gefitinib alone in patients with non-adenocarcinoma (5/13 [39%] v 1/13 [8%], P=0.06). This finding suggests that simvastatin may enhance sensitivity to gefitinib in non-adenocarcinoma that is relatively resistant to gefitinib. Moreover, by Mantha et al.35 demonstrated that the combination of gefitinib and lovastatin showed significant synergic cytotoxic effects in vitro in a total of 16 squamous cell carcinomas, NSCLC, and colon carcinoma cell lines. Of special interest, these cell lines did not possess the activating mutations of EGFR, which confer increased sensitivity to gefitinib. Nevertheless, combining lovastatin with gefitinib induced more significant inhibition of AKT activation than either agent alone. Additionally, lovastatin significantly enhanced the sensitivity to gefitinib treatment regardless PTEN loss in glioblastoma cell lines. These results suggest that statins can augment EGFR inhibition.

老马 发表于 2013-6-18 03:20

                               
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One of the main reasons of resistance to EGFR tyrosine kinase inhibitors (TKIs) is that there are al ...

马哥，对野生型肺鳞癌效果不错，但不知道对肺腺癌怎么样？

谢谢老马，看来2992也只能是一直吃，吃到快耐药再换了。

Clinical perspective of afatinib in non-small cell lung cancer
Clinical perspective of afatinib in non-small cell lung cancer.pdf (669.97 KB, 下载次数: 102)

2013-7-11 16:14 上传

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A Study of Intermittent, High-dose Afatinib to Determine the Maximal Tolerated Dose and Assess Activity of This Dose Against Non-small Cell Lung Cancer With T790M Mutations
http://clinicaltrials.gov/ct2/show/NCT01647711
This trial is divided into Part A and Part B. The primary objective of Part A is to establish the Maximal Tolerated Dose of intermittent high dose afatinib. The primary objective of Part B is to assess the response rate of patients with non-small cell lung cancer with EGFR T790M mutations to a dose of intermittent afatinib established in Part A.

The secondary objective is to explore tumor response and tumor-derived biological markers of response to afatinib, as well as pharmacokinetic parameters of afatinib.

Lung Cancer That Harbors a HER2 Mutation
Lung Cancer That Harbors a HER2 Mutation.PDF (1.28 MB, 下载次数: 110)

2013-7-11 16:25 上传

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绝大多数非小细胞肺癌Her2突变是A775_G776insYVMA（Exon 20）这一类型，突变率为1.7%（3800个病人），一般与EGFR突变或ALK突变或者Kras突变不能共存，只发现有1例与Kras突变共存。
如果病人EGFR突变或ALK突变或者Kras突变为阴性，那么Her2突变概率增加到6%，优势病人特征与EGFR突变相似（女性，不抽烟，腺癌）。
非小细胞肺癌Her2突变病人，腺癌的容易进展，生存期较短；而鳞癌的无影响。
只有少数Her2突变病人有Her2扩增。
非小细胞肺癌中Her2过表达的比例为6-35%，Her2扩增的比例为10-20%。
非小细胞肺癌Her2突变，N线治疗之后，Her2药物治疗的平均有效率约50%，疾病控制率82%，无进展生存期5.1个月，其中Her2单抗联合化疗的疾病控制率为96%，阿法替尼的疾病控制率为100%，而拉帕替尼无效。

http://cancergrace.org/lung/2011 ... -results-in-detail/

Resistance to Afatinib and Cetuximab Combination Therapy in EGFR-mutant Lung Adenocarcinoma
Valentina Pirazzoli1, Ken Takezawa2, Elisa de Stanchina3, William Pao2 and Katerina Politi1
1Department of Pathology and Yale Cancer Center, Yale School of Medicine, New Haven, CT 06520, USA; 2Department of Medicine, Division of Hematology and Oncology, Vanderbilt University, Nashville, TN 37232, USA; 3Antitumor Assessment Core Facility, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA
BACKGROUND
The Epidermal Growth Factor Receptor (EGFR) T790M mutation confers acquired resistance to tyrosine kinase inhibitors (TKIs) in approximately 50% of drug-resistant EGFR mutant lung adenocarcinomas. Experiments using genetically engineered mouse models of EGFR mutant lung cancer have revealed that T790M-mediated resistance can be overcome using a second generation TKI, afatinib, in combin-ation with the anti-EGFR antibody, cetuximab. This drug combination is currently in clinical trials in patients with TKI-resistant tumors and is showing a promising ~ 40% response rate. Nevertheless, cases of afatinib+cetuximab resistance are beginning to emerge.

http://www.yalepath.org/posters/ ... mab_LungAdenoca.htm
Politi_2012_ResistancetoAfatinibCetuximab_LungAdenoca.pdf (1.57 MB, 下载次数: 73)

2013-8-5 23:59 上传

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Combined MET and EGFR inhibition blocks PI3K/AKT and ERK signaling, and restores sensitivity in vitro and in vivo in dacomitinib-resistant tumors
http://imedex.com/lung-cancer-co ... es_Irreversible.pdf

2992有耐药机制么，如果有上抑制剂后，过段时间后会不耐药么