A combination therapy for KRAS-driven lung adenocarcinomas using lipophilic bisphosphonates and rapamycin [electronic resource]

• Ngôn ngữ: eng
• Ký hiệu phân loại: 616.9945 Other diseases
• Thông tin xuất bản: Washington, D.C. : Oak Ridge, Tenn. : United States. Dept. of Energy. Office of Science ; Distributed by the Office of Scientific and Technical Information, U.S. Dept. of Energy, 2014
• Mô tả vật lý: Size: 21 p. : , digital, PDF file.
• Bộ sưu tập: Metadata
• ID: 261298
• Chủ đề: 1. 60 applied life sciences

Tóm tắt

 Lung cancer is the most common human malignancy and leads to about one-third of all cancer-related deaths. Lung adenocarcinomas harboring <
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 KRAS<
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  mutations, in contrast to those with <
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 EGFR<
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  and <
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 EML4-ALK<
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  mutations, have not yet been successfully targeted. Here in this paper, 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-?B 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-?B activation and tumor cell proliferation. Lastly, these results suggest that using lipophilic bisphosphonates in combination with rapamycin may provide an effective strategy for targeting lung adenocarcinomas harboring <
 i>
 KRAS<
 /i>
  mutations.