A combination therapy for KRAS-driven lung adenocarcinomas using lipophilic bisphosphonates and rapamycin.
A combination therapy for KRAS-driven lung adenocarcinomas using lipophilic bisphosphonates and rapamycin.
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DOI：
10.1126/scitranslmed.3010382
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发表时间：
2014-11-19
影响因子：
17.1
通讯作者：
Verma IM
中科院分区：
文献类型：
--
作者：
Xia Y;Liu YL;Xie Y;Zhu W;Guerra F;Shen S;Yeddula N;Fischer W;Low W;Zhou X;Zhang Y;Oldfield E;Verma IM
Lung cancer is the most common human malignancy and leads to about one-third of all cancer-related deaths. Lung adenocarcinomas harboring KRAS mutations, in contrast to those with EGFR and EML4-ALK mutations, have not yet been successfully targeted. Here, we describe a combination therapy for treating these malignancies using two agents: a lipophilic bisphosphonate and rapamycin. This drug combination is much more effective than either agent acting alone in the KRAS G12D induced mouse lung model. Lipophilic bisphosphonates inhibit both farnesyl and geranylgeranyldiphosphate synthases, effectively blocking prenylation of the KRAS and other small G-proteins critical for tumor growth and cell survival. Bisphosphonate treatment of cells initiated autophagy but was ultimately unsuccessful and led to p62 accumulation and concomitant NF-κB activation, resulting in dampened efficacy in vivo. However, we found that rapamycin, in addition to inhibiting the mTOR pathway, facilitated autophagy and prevented p62 accumulation-induced NF-κB activation and tumor cell proliferation. Overall, these results suggest that using lipophilic bisphosphonates in combination with rapamycin may provide an effective strategy for targeting lung adenocarcinomas harboring KRAS mutations.
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通讯作者：
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