生长因子信号通路与乳腺癌内分泌耐药的研究进展

Research progress of growth factor pathway-driven endocrine resistance in breast cancer

肿瘤细胞对内分泌治疗的主要药物他莫昔芬耐药已成为乳腺癌治疗中的一个严重问题。大量研究结果显示，生长因子及其下游的Ras-RabMek-MAPK和P13K-Akt通路过度表达与乳腺癌内分泌治疗耐药密切相关。15％～30％的乳腺癌患者HER2基因通过点突变扩增或过表达，与乳腺癌对各种治疗产生抗性和预后不良密切相关。生长因子可通过基因组和非基因组机制使乳腺癌细胞对雌激素的敏感性增加，极低的雌激素水平也可刺激乳腺癌细胞的增殖。雌激素消除后获得性耐药的高敏状态的共同特征是ERα表达增强、MAPK和PI3K信号活性增强。生长因子信号途径的过表达也可下调ERα的表达和功能，致使乳腺癌细胞对雌激素的非依赖性和对抗雌激素治疗的耐药。因此，靶向生长因子家族及其下游的信号传导通路关键酶类的药物，可以有效地杀灭内分泌耐药的肿瘤细胞。体外研究已发现，吉非替尼可以延迟乳腺癌细胞对雌激素消除的耐药，同时也可显著抑制对他莫昔芬耐药的乳腺癌细胞的增殖。对靶向Ras-Raf-Mek—MAPK途径的法尼基转移酶抑制剂R115777的Ⅱ期临床研究显示，其对内分泌治疗失败的乳腺癌的有效率为24％。临床前研究发现，靶向PI3K—Akt途径的CCI779可以杀灭ER＋的耐药乳腺癌细胞。但由于细胞的信号传导通路是一个相互交联的复杂网络，推测联合用药和靶向多位点的药物也许具有更好的疗效。

Resistance against major endocrine therapy drug, tamoxifen, has been a serious issue in breast cancer treatment. A variety of data show that increased expression of epidermal growth factor receptor （EGFR） ,activation of the mitogen activated protein kinase （MAPK） and PI3K-Akt （ phosphatidylinositol-3-OH kinase） pathway are closely associated with endocrine resistance. Overexpression or loci mutation of HER-2 gene of about 15-30 percent of breast cancer patients is closely correlated with drug assistance and malignant prognosis. Increased growth factor signaling elements contribute to adaptive hypersensitivity in breast cancer cells by inter-play through genomic and non-genomic mechanism. The exquisitely low amounts of estrogen remanet after estrogen deprivation appear sufficient to allow development and maintenance of tumor cell growth. The common characteristics of acquired drug resistance after estrogen deprivation are overexpression of ERa, increased activity of the pathways of MAPK and PI3K. Increased growth factor signaling can also reduce ERα expression and/or function. Not surprisingly, the severe impact of elevated growth factor signaling on expression and function also resultes in estrogen independence and anti-estrogen resistance. Targeted growth factor receptor expression/activation, or key downstream signaling elements can effectively kill acquired-resistant cancer cells. Gefitinib can delay the drug resistance in breast cancer cells after estrogen elimination in vitro, and drastically inhibit proliferation of breast cancer cells resisting against tamoxifen simultaneously. Phase Ⅱ clinical trials demonstrate that R115777, a farnesyltransferase inhibitor, has a 24 percent efficacy in endocrine resistance breast cancer subjects. Preclinical studies show that CCI779, targeting to PI3K-Akt pathway, can eliminate ER＋ resistance breast cancer cells. A variety of signaling pathways appear to constitute a highly integrated network rather than a simple linear structure down a single pathway. Thus, co-targeting therapy and broader target specificity are likely to be a better strategy than narrower targeting.