Carcinogenesis：索拉非尼提高雷帕霉素治疗大肠癌功效

磷酸肌醇3激酶（PI3K）/Akt信号通路的激活与大肠癌的发生和转移密切相关。哺乳动物雷帕霉素靶蛋白(mammalian target of rapamycin，mTOR)是一个重要的丝氨酸/苏氨酸蛋白激酶，mTOR信号通路通过调节细胞周期、蛋白质合成等途径发挥重要的作用，处于生长调节的中心环节，其异常活跃与恶性肿瘤的发生、发展有关。

mTOR是PI3K/Akt信号通路的下游效应因子，主要调控大肠癌的发生和转移，这表明抑制mTOR或许是大肠癌治疗潜在靶标之一。

尽管如此，但许多癌症包括大肠癌都表现出耐雷帕霉素的抗瘤效果。Carcinogenesis杂志上刊登的一项研究中，研究人员证实雷帕霉素抑制mTORC1，导致PI3K/Akt和RAS-MAPK信号通路反馈激活，从而导致肿瘤细胞存活下来，这有可能是大肠癌耐雷帕霉素抗肿瘤活性的机制之一。

但与多激酶抑制剂如索拉非尼相结合试用后，雷帕霉素诱导PI3K/Akt和RAS-MAPK信号通路的激活效应被抑制。索拉非尼联合雷帕霉素协同抑制大肠癌肿瘤细胞的增殖。

由于大肠癌细胞存在KRAS和PIK3CA的突变，所以对雷帕霉素或索拉非尼单药治疗都不甚敏感，但对雷帕霉素和索拉非尼联合治疗却非常敏感。研究证明，联合用药能增强雷帕霉素的疗效，诱导大肠癌细胞凋亡和抑制细胞周期进程，以及迁移和侵袭能力。该研究为雷帕霉素和索拉非尼联合治疗耐受性大肠癌提供了依据。

doi:10.1093/carcin/bgs203
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SORAFENIB ENHANCES THE THERAPEUTIC EFFICACY OF RAPAMYCIN IN COLORECTAL CANCERS HARBORING ONCOGENIC KRAS AND PIK3CA.

Gulhati P, Zaytseva YY, Valentino JD, Stevens PD, Kim JT, Sasazuki T, Shirasawa S, Lee EY, Weiss HL, Dong J, Gao T, Evers BM.

Activation of phosphatidylinositol 3-kinase (PI3K)/Akt signaling is associated with tumorigenesis and metastasis of colorectal cancer (CRC). The mammalian target of rapamycin (mTOR) kinase, a downstream effector of PI3K/Akt signaling, regulates tumorigenesis and metastasis of CRCs, indicating mTOR inhibition may have therapeutic potential. Notwithstanding, many cancers, including CRC, demonstrate resistance to anti-tumorigenic effects of rapamycin. In this study, we show inhibition of mTORC1 with rapamycin leads to feedback activation of PI3K/Akt and Ras-MAPK signaling, resulting in cell survival and possible contribution to rapamycin resistance. Combination with the multi-kinase inhibitor, sorafenib, abrogates rapamycin-induced activation of PI3K/Akt and Ras-MAPK signaling pathways. Combination of rapamycin with sorafenib synergistically inhibits CRC proliferation. CRCs harboring co-existent KRAS and PIK3CA mutations are partially sensitive to either rapamycin or sorafenib monotherapy, but highly sensitive to combination treatment with rapamycin and sorafenib. Combination with sorafenib enhances therapeutic efficacy of rapamycin on induction of apoptosis and inhibition of cell cycle progression, migration and invasion of CRCs. We demonstrate efficacy and safety of concomitant treatment with rapamycin and sorafenib inhibits tumorigenesis of xenografts from CRC cells with co-existent mutations in KRAS and PIK3CA. The efficacy and tolerability of combined treatment with rapamycin and sorafenib provides rationale for use treating CRC patients.