图片来源:www.sciencedaily.com
近日,来自美国科罗拉多大学癌症研究中心的研究人员通过对结直肠癌细胞和动物模型进行研究发现,一种名为TAK-732的药物或具有强大的抗肿瘤活性,在54个所检测的细胞系中有42个细胞系都对该药物敏感,20份肿瘤样本中有15份来自病人机体的肿瘤样本在小鼠机体中都正常生长,这些来自病人机体的肿瘤样本中有9份肿瘤的生长都发生了明显的抑制,这就表明该药物可以明显抑制肿瘤的进展。
Christopher Lieu博士表示,一项大型的临床研究数据表明,该药物具有良好的活性,而且前期的研究数据或许也可以帮助寻找潜在的生物标志物来预测肿瘤是否会对药物TAK-732产生反应。该药物可以干预MAPK信号通路,该信号通路是一种细胞交流的级联信号,可以控制细胞的生长和生存,而且在很多癌症中都会发生频繁的改变,尤其是在黑色素瘤、非小细胞肺癌及结直肠癌中。
药物TAK-732可以通过沉默名为MEK分子的信号肽(关键环节)来发挥作用,缺失MEK分子的活性,MAPK信号就不会发生,而且也不会取代癌细胞的生存和增殖,因此依赖于该途径的癌细胞就会死亡。目前存在很多有效的MEK激酶抑制剂,包括司美替尼(Selumetinib)和曲美替尼(Trametinib)。
研究者Lieu表示,TAK-732的临床前研究数据让人印象非常深刻,我们非常希望TAK-732可以作为新一代的MEK抑制剂来取代当前的药物的使用,本文研究为后期TAK-732药物应用于临床结直肠癌的研究做了一定铺垫,然而由于一些未知情况的出现,该药物在人类机体中使用或许还要面对一些挑战。
很多潜在的癌症药物在使用时都会引发一定的有害副作用,但对于药物TAK-732却并不一定,研究者还需要进行必要的步骤来对该药物进行临床试验的检测,从而来确定该药物药代动力学的一致性。在研究者看来,在结直肠癌中靶向作用MAPK信号通路的方法仍让非常具有潜力,而通过沉默MEK激酶的活性来达到这样的目的似乎是一种非常具有希望的靶点。
最后,研究者希望通过后期更多的努力研究,来利用MEK抑制剂结合其它靶向疗法来进行结直肠癌的治疗。
doi:10.18632/oncotarget.5949
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Antitumor activity of a potent MEK inhibitor, TAK-733, against colorectal cancer cell lines and patient derived xenografts
Christopher H. Lieu1, Peter J. Klauck1, Patrick K. Henthorn1, John J. Tentler1, Aik-Choon Tan1, Anna Spreafico1, Heather M. Selby1, Blair C. Britt1, Stacey M. Bagby1, John J. Arcaroli1, Wells A. Messersmith1, Todd M. Pitts1 and S. Gail Eckhardt1
Background: CRC is a significant cause of cancer mortality, and new therapies are needed for patients with advanced disease. TAK-733 is a highly potent and selective investigational novel MEK allosteric site inhibitor. Materials and Methods: In a preclinical study of TAK-733, a panel of CRC cell lines were exposed to varying concentrations of the agent for 72 hours followed by a sulforhodamine B assay. Twenty patient-derived colorectal cancer xenografts were then treated with TAK-733 in vivo. Tumor growth inhibition index (TGII) was assessed to evaluate the sensitivity of the CRC explants to TAK-733 while linear regression was utilized to investigate the predictive effects of genotype on the TGII of explants. Results: Fifty-four CRC cell lines were exposed to TAK-733, while 42 cell lines were deemed sensitive across a broad range of mutations. Eighty-two percent of the cell lines within the sensitive subset were BRAF or KRAS/NRAS mutant, wheras 80% of the cell lines within the sensitive subset were PIK3CA WT. Twenty patient-derived human tumor CRC explants were then treated with TAK-733. In total, 15 primary human tumor explants were found to be sensitive to TAK-733 (TGII ≤ 20%), including 9 primary human tumor explants that exhibited tumor regression (TGII > 100%). Explants with a BRAF/KRAS/NRAS mutant and PIK3CA wild-type genotype demonstrated increased sensitivity to TAK-733 with a median TGII of -6%. MEK-response gene signatures also correlated with responsiveness to TAK-733 in KRAS-mutant CRC. Conclusions: The MEK inhibitor TAK-733 demonstrated robust antitumor activity against CRC cell lines and patient-derived tumor explants. While the preclinical activity observed in this study was considerable, single-agent efficacy in the clinic has been limited in CRC, supporting the use of these models in an iterative manner to elucidate resistance mechanisms that can guide rational combination strategies.