GDC-0980 Is a Novel Class I PI3K/mTOR Kinase Inhibitor with Robust Activity in Cancer Models Driven by the PI3K Pathway
GDC-0980 Is a Novel Class I PI3K/mTOR Kinase Inhibitor with Robust Activity in Cancer Models Driven by the PI3K Pathway
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DOI：
10.1158/1535-7163.mct-11-0446
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发表时间：
2011-12-01
影响因子：
5.7
通讯作者：
Friedman, Lori S.
中科院分区：
文献类型：
--
作者：
Wallin, Jeffrey J.;Edgar, Kyle A.;Friedman, Lori S.
磷酸肌醇-3激酶(PI3K)/Akt信号通路的改变通过多种机制在癌症中广泛发生，包括PIK3CA基因突变、磷酸酶和紧张素同源物（PTEN）的缺失或突变，以及哺乳动物雷帕霉素靶蛋白（mTOR）复合物的解除管制。该通路的失调与肿瘤发生、细胞生长和存活、侵袭和血管生成有关，因此，PI3K和mTOR是有希望的癌症治疗靶点。GDC-0980是一类PI3激酶和mTOR激酶（TORC1/2）的选择性强效口服抑制剂，具有良好的药代动力学和药学性质。通过药效学（PD）生物标志物测量，GDC-0980有效抑制PI3K和mTOR下游的信号转导，从而作用于两个关键通路节点，对通路中的信号传导产生最强的抑制作用。相应的，GDC-0980在广泛的癌细胞系中都是有效的，在乳腺癌、前列腺癌和肺癌中具有最大的效力，在黑色素瘤和胰腺癌中活性较低，与KRAS和BRAF作为耐药标记相一致。用GDC-0980治疗癌细胞导致G1细胞周期阻滞，与mTOR抑制剂不同，GDC-0980诱导某些癌细胞凋亡，包括那些通过PI3K和PTEN直接途径激活的癌细胞。低剂量GDC-0980有效抑制异种移植物模型中的肿瘤生长，包括PI3K活化、LKB1或PTEN缺失的异种移植物模型，并引起PD生物标志物的暴露相关降低。这些临床前数据表明，GDC-0980是一种有效的双PI3K/mTOR抑制剂，具有临床应用前景。巨蟹座；10 (12);2426 - 36。AACR (C) 2011。
Alterations of the phosphoinositide-3 kinase (PI3K)/Akt signaling pathway occur broadly in cancer via multiple mechanisms including mutation of the PIK3CA gene, loss or mutation of phosphatase and tensin homolog (PTEN), and deregulation of mammalian target of rapamycin (mTOR) complexes. The dysregulation of this pathway has been implicated in tumor initiation, cell growth and survival, invasion and angiogenesis, thus, PI3K and mTOR are promising therapeutic targets for cancer. We discovered GDC-0980, a selective, potent, orally bioavailable inhibitor of Class I PI3 kinase and mTOR kinase (TORC1/2) with excellent pharmacokinetic and pharmaceutical properties. GDC-0980 potently inhibits signal transduction downstream of both PI3K and mTOR, as measured by pharmacodynamic (PD) biomarkers, thereby acting upon two key pathway nodes to produce the strongest attainable inhibition of signaling in the pathway. Correspondingly, GDC-0980 was potent across a broad panel of cancer cell lines, with the greatest potency in breast, prostate, and lung cancers and less activity in melanoma and pancreatic cancers, consistent with KRAS and BRAF acting as resistance markers. Treatment of cancer cell lines with GDC-0980 resulted in G1 cell-cycle arrest, and in contrast to mTOR inhibitors, GDC-0980 induced apoptosis in certain cancer cell lines, including those with direct pathway activation via PI3K and PTEN. Low doses of GDC-0980 potently inhibited tumor growth in xenograft models including those with activated PI3K, loss of LKB1 or PTEN, and elicited an exposure-related decrease in PD biomarkers. These preclinical data show that GDC-0980 is a potent and effective dual PI3K/mTOR inhibitor with promise for the clinic. Mol Cancer Ther; 10(12); 2426-36. (C)2011 AACR.