Cell:抑制TAK1蛋白促進結腸癌細胞凋亡

近日，美國波士頓大學醫學院藥理學和實驗療法部助理教授Anurag Singh博士在芝加哥召開的美國癌症研究屆年會上公布了他最近有關靶向治療結腸癌的工作進展。相關研究論文發表在Cell雜誌上。

每年，有超過一百萬的結腸癌病例被確診，在全世界範圍內結腸癌會造成約60萬人死亡。這些病例中有一半以上發現有KRAS基因的突變。在美國，結腸癌患者的KRAS基因突變是非常常見的，但靶向KRAS基因的治療藥物臨床效益卻不甚樂觀。因此，KRAS基因突變的患者通常都面臨非常有限的治療選擇，並且臨床預後很差。

Singh和他的同事們已經確定了KRAS基因突變的結腸癌中處於過度激活的一些基因。其中包括MAP3K7或TAK1蛋白基因，這兩蛋白在促進結腸癌病情惡化中起著非常關鍵的作用。抑制TAK1蛋白的結果是殺死KRAS基因突變的腫瘤細胞，但對正常非突變的細胞影響很小。Singh說：抗TAK1的蛋白拮抗劑可能為侵略性的KRAS基因突變的結腸癌患者提供「個性化」醫學治療。研究人員目前正努力測試TAK1蛋白抑制劑的臨床療效。（生物谷：Bioon）

TAK1 Inhibition Promotes Apoptosis in KRAS-Dependent Colon Cancers

Anurag Singh, Michael F. Sweeney, Min Yu, Alexa Burger, Patricia Greninger, Cyril Benes, Daniel A. Haber, Jeff Settleman

Colon cancers frequently harbor KRAS mutations, yet only a subset of KRAS mutant colon cancer cell lines are dependent upon KRAS signaling for survival. In a screen for kinases that promote survival of KRAS-dependent colon cancer cells, we found that the TAK1 kinase (MAP3K7) is required for tumor cell viability. The induction of apoptosis by RNAi-mediated depletion or pharmacologic inhibition of TAK1 is linked to its suppression of hyperactivated Wnt signaling, evident in both endogenous and genetically reconstituted cells. In APC mutant/KRAS-dependent cells, KRAS stimulates BMP-7 secretion and BMP signaling, leading to TAK1 activation and enhancement of Wnt-dependent transcription. An in vitro-derived TAK1 dependency signature is enriched in primary human colon cancers with mutations in both APC and KRAS, suggesting potential clinical utility in stratifying patient populations. Together, these findings identify TAK1 inhibition as a potential therapeutic strategy for a treatment-refractory subset of colon cancers exhibiting aberrant KRAS and Wnt pathway activation.