磷酸肌醇3激酶（PI3K）/Akt信號(hào)通路的激活與大腸癌的發(fā)生和轉(zhuǎn)移密切相關(guān),。哺乳動(dòng)物雷帕霉素靶蛋白(mammalian target of rapamycin,，mTOR)是一個(gè)重要的絲氨酸/蘇氨酸蛋白激酶，mTOR信號(hào)通路通過調(diào)節(jié)細(xì)胞周期,、蛋白質(zhì)合成等途徑發(fā)揮重要的作用,，處于生長調(diào)節(jié)的中心環(huán)節(jié)，其異常活躍與惡性腫瘤的發(fā)生,、發(fā)展有關(guān),。
mTOR是PI3K/Akt信號(hào)通路的下游效應(yīng)因子，主要調(diào)控大腸癌的發(fā)生和轉(zhuǎn)移,，這表明抑制mTOR或許是大腸癌治療潛在靶標(biāo)之一,。
盡管如此，但許多癌癥包括大腸癌都表現(xiàn)出耐雷帕霉素的抗瘤效果,。Carcinogenesis雜志上刊登的一項(xiàng)研究中,，研究人員證實(shí)雷帕霉素抑制mTORC1，導(dǎo)致PI3K/Akt和RAS-MAPK信號(hào)通路反饋激活,，從而導(dǎo)致腫瘤細(xì)胞存活下來,，這有可能是大腸癌耐雷帕霉素抗腫瘤活性的機(jī)制之一。
但與多激酶抑制劑如索拉非尼相結(jié)合試用后,，雷帕霉素誘導(dǎo)PI3K/Akt和RAS-MAPK信號(hào)通路的激活效應(yīng)被抑制,。索拉非尼聯(lián)合雷帕霉素協(xié)同抑制大腸癌腫瘤細(xì)胞的增殖。
由于大腸癌細(xì)胞存在KRAS和PIK3CA的突變,，所以對(duì)雷帕霉素或索拉非尼單藥治療都不甚敏感,，但對(duì)雷帕霉素和索拉非尼聯(lián)合治療卻非常敏感。研究證明,，聯(lián)合用藥能增強(qiáng)雷帕霉素的療效,，誘導(dǎo)大腸癌細(xì)胞凋亡和抑制細(xì)胞周期進(jìn)程，以及遷移和侵襲能力,。該研究為雷帕霉素和索拉非尼聯(lián)合治療耐受性大腸癌提供了依據(jù)。（生物谷：Bioon.com）
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.
