Combining a PI3K inhibitor with a PARP inhibitor provides an effective therapy for BRCA1-related breast cancer.
Combining a PI3K inhibitor with a PARP inhibitor provides an effective therapy for BRCA1-related breast cancer.
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DOI：
10.1158/2159-8290.cd-11-0336
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发表时间：
2012-11
期刊：
影响因子：
28.2
通讯作者：
Wulf GM
中科院分区：
文献类型：
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作者：
Juvekar A;Burga LN;Hu H;Lunsford EP;Ibrahim YH;Balmañà J;Rajendran A;Papa A;Spencer K;Lyssiotis CA;Nardella C;Pandolfi PP;Baselga J;Scully R;Asara JM;Cantley LC;Wulf GM
需要改进转移性乳腺癌的治疗。在这里，我们显示了在MMTV-CreBRCA 1f/fp 53 +/−小鼠乳腺癌模型中磷酸肌醇3-激酶（PI 3 K）和MAP激酶（MAPK）通路的激活。当用泛IA类PI 3 K抑制剂NVP-BKM 120治疗时，肿瘤倍增从5天延迟至26天。NVP-BKM 120减少AKT磷酸化、肿瘤细胞增殖和血管生成。耐药肿瘤维持AKT磷酸化的抑制，但在“推缘”处表现出MAPK通路的激活。令人惊讶的是，PI 3 K抑制增加了DNA损伤，聚ADP核糖基化和γ H2 AX的指标，但减少了Rad 51焦点形成，表明PI 3 K活性对Rad 51募集的关键作用。PARP抑制剂奥拉帕尼单独适度减弱肿瘤生长;然而，NVP-BKM 120和奥拉帕尼的组合在小鼠模型中将肿瘤倍增延迟至70天以上，在来自人BRCA 1相关肿瘤的异种移植物中延迟至50天以上，这表明组合的PI 3 K和PARP抑制可能是BRCA 1相关肿瘤的有效治疗。
There is a need to improve treatments for metastatic breast cancer. Here we show activation of the phosphoinositide 3-kinase (PI3K) and MAP kinase (MAPK) pathways in a MMTV-CreBRCA1f/fp53+/− mouse model of breast cancer. When treated with the pan-Class IA PI3K-inhibitor NVP-BKM120, tumor doubling was delayed from 5 to 26 days. NVP-BKM120 reduced AKT phosphorylation, tumor cell proliferation and angiogenesis. Resistant tumors maintained suppression of AKT phosphorylation but exhibited activation of the MAPK-pathway at the “pushing margin”. Surprisingly, PI3K-inhibition increased indicators of DNA damage, poly-ADP-ribosylation and γH2AX, but decreased Rad51 focus formation, suggesting a critical role of PI3K activity for Rad51 recruitment. PARP-inhibitor Olaparib alone attenuated tumor growth modestly; however, the combination of NVP-BKM120 and Olaparib delayed tumor doubling to more than 70 days in the mouse model and over 50 days in xenotransplants from human BRCA1-related tumors, suggesting that combined PI3K- and PARP-inhibition might be effective treatment for BRCA1-related tumors.