SRC抑制剂塞卡替尼saracatinib对付ALK耐药

Patient-derived models of acquired resistance can identify effective drug combinations for cancer
http://www.sciencemag.org/conten ... /12/science.1254721
Adam S. Crystal, Alice T. Shaw等。
Targeted cancer therapies have produced substantial clinical responses, but most tumors develop resistance to these drugs. Here, we describe a pharmacogenomic platform that facilitates rapid discovery of drug combinations that can overcome resistance. We established cell culture models derived from biopsy samples of lung cancer patients whose disease had progressed while on treatment with EGFR or ALK tyrosine kinase inhibitors and then subjected these cells to genetic analyses and a pharmacological screen. Multiple effective drug combinations were identified. For example, the combination of ALK and MEK inhibitors was active in an ALK-positive resistant tumor that had developed a MAP2K1 activating mutation, and the combination of EGFR and FGFR inhibitors was active in an EGFR mutant resistant cancer with a novel mutation in FGFR3. Combined ALK and SRC inhibition was effective in several ALK-driven patient-derived models, a result not predicted by genetic analysis alone. With further refinements, this strategy could help direct therapeutic choices for individual patients.

http://hms.harvard.edu/news/screening-out-resistances
“several [six] other ALK-positive tumors were re-sensitized by drugs that inhibit SRC enzymes, even though no SRC-related mutations were present. Further evidence indicated that inhibiting ALK led to activation of SRC-controlled pathways that promoted resistance.

The scientists also found that combining ALK and SRC inhibitors as first-line therapy might delay the emergence of resistance. The efficacy of this combination was demonstrated in multiple mouse models.

“We expected effective combinations to be specific against particular cell lines rather than broadly active, and this is largely what we found,” said Cyril Benes, HMS assistant professor of medicine at Mass General and co-senior author of the report. “The broad activity of the combination of ALK and SRC inhibitors across ALK-driven models suggests this may be a common, previously unsuspected resistance mechanism. We were able to validate four of these combinations in animal models, but many more were indicated across the cell lines that we tested.”
The SRC family belongs to nonreceptor tyrosine kinases. SRC was originally identified as a transforming protein of the Rous sarcoma virus (RSV) that had enzymatic ability to phosphorylate tyrosine in protein substrates. SRC is overexpressed and activated in a large number of human malignancies and has been linked to the development of cancer and progression to distant metastases. In addition to increasing cell proliferation, a key role of SRC in cancer seems to be the ability to promote invasion and motility, functions that might contribute to tumor progression.

Examples

saracatinib (AZD0530), an orally available Src inhibitor, demonstrated potent antimigratory and anti-invasive effects in vitro, and inhibited metastasis in a murine model of bladder cancer.

Dasatinib produced by Bristol-Myers Squibb and sold under the trade name Sprycel.

Bosutinib has been developed for the treatment of chronic myelogenous leukemia by Pfizer.

中文名称        塞卡替尼
别名        N-(5-氯-1,3-苯并二氧戊环-4-基)-7-[2-(4-甲基-1-哌嗪基)乙氧基]-5-[(四氢-2H-吡喃-4-基)氧基]-4-喹唑啉胺;
英文名称        Saracatinib
英文别名        saracatinib;N-(5-Chloro-1,3-benzodioxol-4-yl)-7-[2-(4-methyl-1-piperazinyl)ethoxy]-5-[(tetrahydro-2H-pyran-4-yl)oxy]-4-quinazolinamine
CAS NO.        379231-04-6
分子式        C27H32CLN5O5
分子量  542.03
Saracatinib (AZD0530)是一种有效的Src抑制剂，IC50为2.7 nM，对c-Yes， Fyn， Lyn， Blk， Fgr和Lck等也有活性；但对Abl和EGFR (L858R和L861Q)活性较低。Phase 2/3。
Saracatinib也有效抑制其他Src酪氨酸激酶家族成员，包括c-Yes, Fyn, Lyn, Blk, Fgr, 和Lck，IC50为4到10 nM。Saracatinib有效抑制SrcY530F突变的NIH 3T3细胞，IC50为80 nM。在NBT-II膀胱癌细胞中，Saracatinib显著阻断HT1080细胞通过立体骨胶原基质的入侵，且完全抑制EGF诱导的细胞分散。Saracatinib作用于DU145和PC3细胞，通过抑制Y419磷酸化而有效抑制Src激活。Saracatinib抑制前列腺癌包括PC3, DU145, CWR22Rv1和 LNCaP的生长，而Saracatinib作用于 LAPC-4, PZ-HPV7和RWPE-1细胞时却显示低活性。Saracatinib使细胞周期停止在G1/S期，但是不使caspase 3断裂。Saracatinib 也明显抑制Boyden小室的DU145和PC3 移动。[2]Saracatinib有效且持久抑制Akt，且增强A549和Calu-6细胞对放射处理的敏感性。Saracatinib在活性，再吸收，及组成上抑制蚀骨细胞。Saracatinib也可逆阻断蚀骨细胞前体的移动。

A Randomised Phase II Trial of Saracatinib Versus Placebo for Cancer-induced Bone Pain
A phase II trial of saracatinib, an inhibitor of src kinases, in previously-treated advanced non-small-cell lung cancer: the princess margaret hospital phase II consortium.
http://www.ncbi.nlm.nih.gov/pubmed/24169259
Abstract
BACKGROUND:
The src family of kinases may play a role in the malignant phenotype through effects on migration, motility, adhesion and proliferation. The activity of saracatinib, an orally available inhibitor of src kinases, was evaluated in patients with advanced, platinum-pretreated NSCLC.
PATIENTS AND METHODS:
Eligible patients with advanced NSCLC of any histologic subtype and who had obtained a best response to prior platinum-based chemotherapy of at least stable disease received saracatanib 175 mg orally daily in a 28 day cycle. The primary end point was the proportion of patients progression-free after 4 cycles (16 weeks) of therapy; 8 such patients of 32 evaluable were required to deem the therapy active. Immunohistochemistry for src expression was performed on archival tissue from enrolled patients.
RESULTS:
Thirty-seven patients received a median of 2 cycles (range, 1-14) each. Six of 31 evaluable patients were progression-free at 16 weeks. Two partial responses were observed, lasting 3.7 and 14.6 months; 1 responder had an EGFR exon 19 deletion. An additional 4 patients had stable disease for at least 4 cycles. The median progression-free and overall survival times were 1.8 and 7.6 months. No correlation between src protein expression and outcome was observed.
CONCLUSIONS:
There may be a subset of saracatinib-responsive NSCLC that is currently molecularly undefined. Further studies of this agent in a population preselected for target mutations that potentially relevant to src pathways, such as EGFR, should be considered.

Clin Cancer Res. 2010 Oct 1;16(19):4876-83. doi: 10.1158/1078-0432.CCR-10-0748. Epub 2010 Aug 30.
Phase I safety, pharmacokinetics, and inhibition of SRC activity study of saracatinib in patients with solid tumors.
Baselga J1, Cervantes A, Martinelli E, Chirivella I, Hoekman K, Hurwitz HI, Jodrell DI, Hamberg P, Casado E, Elvin P, Swaisland A, Iacona R, Tabernero J.
Author information
Abstract
PURPOSE:
This dose-escalation study evaluated the safety, tolerability, and pharmacokinetics (PK) of the oral Src inhibitor saracatinib (AZD0530) in patients with advanced solid malignancies. Tumor biopsy samples were taken to investigate the effect of saracatinib on Src activity in tumors.
EXPERIMENTAL DESIGN:
Part A of the study followed a multiple-ascending dose design to establish the maximum tolerated dose (MTD) of saracatinib. Part B was a randomized, parallel-group, cohort-expansion phase to further assess tolerated doses. Safety, tolerability, and Src activity (immunohistochemistry and lysate-based methodologies) were assessed after 21 days of once-daily oral dosing. PK was assessed after single and multiple dosing.
RESULTS:
In part A, 30 patients received once-daily saracatinib at doses of 60 to 250 mg; the MTD was established as 175 mg. In part B, 51 patients were randomized to receive 50 mg (n = 16), 125 mg (n = 16), or 175 mg (n = 19) of saracatinib. The most common grade ≥3 events considered to be treatment related were anemia, diarrhea, and asthenia. Tumor Src activity was reduced following saracatinib treatment. The area under the concentration-time curve and C(max) of saracatinib increased with increasing dose. Saracatinib accumulated 4- to 5-fold on once-daily dosing to reach steady-state exposure after 10 to 17 days of dosing. The half-life was ～40 hours.
CONCLUSIONS:
Saracatinib was well tolerated in patients with advanced solid malignancies. A reduction in tumor Src activity was observed. PK data show that saracatinib is suitable for once-daily oral dosing. Based on this study, the recommended dose for the phase II studies was chosen to be 175 mg/d.
©2010 AACR.
http://www.ncbi.nlm.nih.gov/pubmed/20805299?dopt=Abstract
主要3级副作用是：腹泻，贫血，乏力。

Bone. 2012 Apr;50(4):885-92. doi: 10.1016/j.bone.2011.12.017. Epub 2012 Jan 8.
Effects of Src kinase inhibition by saracatinib (AZD0530) on bone turnover in advanced malignancy in a Phase I study.
Hannon RA1, Finkelman RD, Clack G, Iacona RB, Rimmer M, Gossiel F, Baselga J, Eastell R.
Author information
Abstract
Saracatinib (AZD0530) is an orally active once-daily Src kinase inhibitor which modulates key signaling pathways in cancer cells. In a Phase I study in patients with advanced solid malignancies resistant to standard treatment we assessed the effect of saracatinib on bone turnover. Fifty-one patients were randomized into three parallel groups to receive saracatinib 50, 125 or 175 mg/day. After a single dose followed by a 7-day washout, patients received once-daily doses for 21 days. Bone turnover markers were measured in serum and urine samples collected before dosing on days 1, 2, 3, 17 and 28. Samples were available at baseline and more than one other time point for 44 patients. Bone resorption markers were significantly decreased by saracatinib. Serum cross-linked C-terminal telopeptide of type I collagen (sCTX) changed in the 50, 125 and 175 mg/day groups by -36% (95% CI -58, -4), -64% (95% CI -75, -48) and -75% (95% CI -83, -61), respectively, at day 28. Urinary cross-linked N-terminal telopeptide of type I collagen/creatinine ratio (uNTX/Cr) changed in the 50, 125 and 175 mg/day groups by; -13% (95% CI -33, 13), -48% (95% CI -59, -34) and -50% (95% CI -62, -35), respectively, at day 28. The significant decreases in bone resorption markers indicate that suppression of Src kinase inhibits osteoclast activity in patients with advanced cancer. This result suggests that saracatinib may have therapeutic benefit in metastatic bone disease.
http://www.ncbi.nlm.nih.gov/pubmed/22245630

Study to Evaluate the Safety and Effects AZD0530 on Prostate and Breast Cancer Subjects With Metastatic Bone Disease
临床结果：
http://www.clinicaltrial.gov/ct2 ... amp;sect=X01256#all

AZD0530 in Treating Patients With Extensive Stage Small Cell Lung Cancer
临床结果：
http://www.clinicaltrial.gov/ct2 ... catinib&rank=11

英文看不懂吖

老马还在为论坛做贡献！{:soso_e179:}{:soso_e183:}

Src及其抑制剂对非小细胞肺癌作用的研究进展.pdf (362.35 KB, 下载次数: 31)

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src激酶抑制剂综述.rar (62.2 KB, 下载次数: 22)

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马哥，alkinhibitors.com这个网站我翻墙都打不开了。。。

A phase II trial of saracatinib, an inhibitor of src kinases, in previously-treated advanced non-small-cell lung cancer:
laurie2014.pdf (204.89 KB, 下载次数: 12)

2014-11-22 21:12 上传

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这款药能抑制骨转的嘛

SRC还在RAS之前啊，MEK这条通路的。但好像之前都没怎么去关注它

AZD0530，对小细胞也有效？？