生物谷报道：新研究提出一个也许能改进一类抗癌新药效果的方法。这些被称为“靶向治疗”(targetedtherapies)的药物通过抑制单个受体酪氨酸蛋白激酶(RTKs)的活性而起作用，RTKs是帮助驱动癌细胞失控生长的信号发生蛋白质。这类疗法在临床试验中显示了可观的前景，但是某些固体肿瘤，包括一种侵犯性强的脑瘤——多形性胶质母细胞瘤，对疗法的反应不理想。JayneStommel和同事用动物肿瘤模型的实验发现，许多不同的RTKs在多形性胶质母细胞瘤中过度激活，如果不是针对一个RTK的单一药物，而用针对多个RTKs的药物组合来治疗肿瘤，疗效要更好。这个方法对人类肿瘤的效果可以用临床试验来检验。（科学时报）
原始出处:
Published Online September 13, 2007
Science DOI: 10.1126/science.1142946
Submitted on March 23, 2007
Accepted on August 31, 2007
Coactivation of Receptor Tyrosine Kinases Affects the Response of Tumor Cells to Targeted Therapies
Jayne M. Stommel 1, Alec C. Kimmelman 1, Haoqiang Ying 1, Roustem Nabioullin 1, Aditya H. Ponugoti 1, Ruprecht Wiedemeyer 1, Alexander H. Stegh 1, James E. Bradner 1, Keith L. Ligon 1, Cameron Brennan 2, Lynda Chin 1, Ronald A. DePinho 1*
1 Departments of Medical Oncology, Medicine, Dermatology, Pathology, and Genetics, Belfer Institute, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, USA.
2 Department of Neurosurgery, Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA.
* To whom correspondence should be addressed.
Ronald A. DePinho , E-mail: ron_depinho@dfci.harvard.edu
Targeted therapies that inhibit receptor tyrosine kinases (RTKs) and the downstream phosphatidylinositol 3-kinase (PI3K) signaling pathway have shown promising anti-cancer activity, but their efficacy in the brain tumor glioblastoma multiforme (GBM) and other solid tumors has been modest. We hypothesized that multiple RTKs are co-activated in these tumors and that redundant inputs drive and maintain downstream signaling, thereby limiting the efficacy of therapies targeting single RTKs. Tumor cell lines, xenotransplants, and primary tumors indeed show multiple concomitantly activated RTKs. Combinations of RTK inhibitors and/or RNAi, but not single agents, decreased signaling, cell survival, and anchorage-independent growth even in glioma cells deficient in PTEN, a frequently inactivated inhibitor of PI3K. Thus, effective GBM therapy may require combination regimens targeting multiple RTKs.
