Cell Death Regulation Laboratory, Department of Medicine, and Department of Pathology, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
Clin Cancer Res. 2011 Aug 1;17(15):5005-15. doi: 10.1158/1078-0432.CCR-11-0099. Epub 2011 Jun 8.
Metastatic breast cancer is a deadly disease which requires new therapeutic strategies. Endogenous TNF-related apoptosis-inducing ligand (TRAIL) functions as a metastasis suppressor by activating proapoptotic TRAIL receptors (TRAIL-R1/DR4 and/or TRAIL-R2/DR5) in transformed cells, making it an attractive pathway for antimetastatic therapies. However, it is unclear whether TRAIL-R1 or TRAIL-R2 is a better therapeutic target in metastatic breast cancer.
Several metastatic, triple (estrogen receptor, progesterone receptor, and HER2)-negative cancer cell lines were treated with human agonistic monoclonal antibodies targeting TRAIL-R1 (mapatumumab) or TRAIL-R2 (lexatumumab). The effects on cell viability, apoptosis, and caspase-8 activation were determined. An orthotopic model of triple-negative breast cancer in which fluorescently labeled breast cancer cells metastasize from the mammary gland to lymph nodes and lung was utilized to evaluate the effects of mapatumumab, lexatumumab, or doxorubicin on primary and metastatic tumor burden in vivo.
Lexatumumab was more effective than mapatumumab in activating caspase-8, inducing apoptosis and inhibiting long-term survival of metastatic cancer cells, which expressed both TRAIL-R1 and TRAIL-R2. Human mammary epithelial cells transformed by oncogenic Ras were more sensitive to lexatumumab than nontransformed cells. Lexatumumab inhibited lymph node and lung metastases more robustly than mapatumumab in an orthotopic model of triple-negative breast cancer; both agents inhibited mammary tumor growth. In addition, lexatumumab was more effective than doxorubicin at suppressing metastases at doses of doxorubicin that were associated with toxicity, even though doxorubicin reduced primary tumor burden more robustly than lexatumumab.
Targeting TRAIL-R2 receptor may be an effective therapeutic strategy for metastatic breast cancer.
转移性乳腺癌是一种致命疾病，需要新的治疗策略。内源性肿瘤坏死因子相关凋亡诱导配体（TRAIL）通过在转化细胞中激活促凋亡的 TRAIL 受体（TRAIL-R1/DR4 和/或 TRAIL-R2/DR5）发挥转移抑制作用，使其成为抗转移治疗的有吸引力的途径。然而，TRAIL-R1 或 TRAIL-R2 是否是转移性乳腺癌更好的治疗靶点尚不清楚。
用针对 TRAIL-R1（mapatumumab）或 TRAIL-R2（lexatumumab）的人源激动性单克隆抗体处理几种转移性、三阴性（雌激素受体、孕激素受体和 HER2）阴性癌细胞系。测定对细胞活力、凋亡和半胱天冬酶-8 激活的影响。利用三阴性乳腺癌的原位模型，其中荧光标记的乳腺癌细胞从乳腺转移到淋巴结和肺，评估 mapatumumab、lexatumumab 或多柔比星对体内原发性和转移性肿瘤负担的影响。
与 mapatumumab 相比，lexatumumab 更有效地激活 caspase-8、诱导凋亡并抑制表达 TRAIL-R1 和 TRAIL-R2 的转移性癌细胞的长期存活。致癌 Ras 转化的人乳腺上皮细胞比非转化细胞对 lexatumumab 更敏感。在三阴性乳腺癌的原位模型中，lexatumumab 比 mapatumumab 更能抑制淋巴结和肺转移；两种药物均抑制乳腺肿瘤生长。此外，在与毒性相关的多柔比星剂量下，lexatumumab 比多柔比星更有效地抑制转移，尽管多柔比星比 lexatumumab 更有效地减少原发性肿瘤负担。
靶向 TRAIL-R2 受体可能是转移性乳腺癌的有效治疗策略。
