PI3K Pathway Activation Mediates Resistance to MEK Inhibitors in KRAS Mutant Cancers
PI3K Pathway Activation Mediates Resistance to MEK Inhibitors in KRAS Mutant Cancers
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DOI：
10.1158/0008-5472.can-08-4765
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发表时间：
2009-05-15
期刊：
影响因子：
11.2
通讯作者：
Stegmeier, Frank
中科院分区：
文献类型：
--
作者：
Wee, Susan;Jagani, Zainab;Stegmeier, Frank
RAS通路是癌症中最常见的非调控通路之一。RAS信号通过多条效应通路传递，包括RAF/MAPK/ERK/ERK MAPK/ERK MAPK和PI3K-AKT信号通路。BBAF和PIK3CA的激活突变以及PI3K的负调控因子抑癌基因PTEA的功能丧失突变的频繁出现，说明了这些效应通路的致癌潜力。以前的研究发现，BRAF突变的癌症对MEK抑制高度敏感，而RAS突变的癌症表现出更不同的反应。造成这种异质性反应的分子机制尚不清楚。在本研究中，我们发现PI3K通路的激活强烈影响RAS突变细胞对MEK抑制剂的敏感性。PIK3CA的激活突变降低了对MEK抑制的敏感性，而PTEN突变似乎导致完全耐药。我们进一步表明，PIK3CA的下调使KRAS和PIK3CA突变共存的细胞对MEK抑制重新敏感。在分子水平上，这两条通路的双重抑制似乎是完全抑制雷帕霉素效应通路下游哺乳动物靶标并导致细胞死亡所必需的。最后，我们表明，虽然MEK或PI3K通路的失活会导致部分肿瘤生长抑制，但需要有针对性地抑制这两个通路才能实现肿瘤停滞。我们的研究提供了有助于解释KRAS突变癌症对MEK途径抑制的异质性反应的分子洞察力，并为MEK和PI3K联合靶向治疗的临床测试提供了强有力的理论基础。[癌症资源2009：69(10)：4286-93]
The RAS pathway is one of the most frequently deregulated pathways in cancer. RAS signals through multiple effector pathways, including the RAF/mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) kinase (MEK)/ERK MAPK and phosphatidylinositol 3-kinase (PI3K)-AKT signaling cascades. The oncogenic potential of these effector pathways is illustrated by the frequent occurrence of activating mutations in BBAF, and PIK3CA as well as loss-of-function mutations in the tumor suppressor PTEA,, a negative regulator of PI3K. Previous studies have found that whereas BRAF mutant cancers are highly sensitive to MEK inhibition, RAS mutant cancers exhibit a more variable response. The molecular mechanisms responsible for this heterogeneous response remain unclear. In this study, we show that PI3K pathway activation strongly influences the sensitivity of RAS mutant cells to MEK inhibitors. Activating mutations in PIK3CA reduce the sensitivity to MEK inhibition, whereas PTEN mutations seem to cause complete resistance. We further show that down-regulation of PIK3CA resensitizes cells with co-occurring KRAS and PIK3CA mutations to MEK inhibition. At the molecular level, the dual inhibition of both pathways seems to be required for complete inhibition of the downstream mammalian target of rapamycin effector pathway and results in the induction of cell death. Finally, we show that whereas inactivation of either the MEK or PI3K pathway leads to partial tumor growth inhibition, targeted inhibition of both pathways is required to achieve tumor stasis. Our study provides molecular insights that help explain the heterogeneous response of KRAS mutant cancers to MEK pathway inhibition and presents a strong rationale for the clinical testing of combination MEK and PI3K targeted therapies. [Cancer Res 2009:69(10):4286-93]