TY - JOUR
T1 - A combination therapy for kras-Driven lung adenocarcinomas using lipophilic bisphosphonates and rapamycin
AU - Xia, Yifeng
AU - Liu, Yi Liang
AU - Xie, Yonghua
AU - Zhu, Wei
AU - Guerra, Francisco
AU - Shen, Shen
AU - Yeddula, Narayana
AU - Fischer, Wolfgang
AU - Low, William
AU - Zhou, Xiaoying
AU - Zhang, Yonghui
AU - Oldfield, Eric
AU - Verma, Inder M.
PY - 2014/11/19
Y1 - 2014/11/19
N2 - 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 been successfully targeted. We describe a combination therapy for treating these malignancies with 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 KRAS and other small G proteins (heterotrimeric GTP-binding protein, heterotrimeric guanine nucleotide-binding 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 nuclear factor kB (NF-kB) activation, resulting in dampened efficacy in vivo. However, we found that rapamycin, in addition to inhibiting the mammalian target of rapamycin (mTOR) pathway, facilitated autophagy and prevented p62 accumulation-induced NF-kB 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.
AB - 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 been successfully targeted. We describe a combination therapy for treating these malignancies with 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 KRAS and other small G proteins (heterotrimeric GTP-binding protein, heterotrimeric guanine nucleotide-binding 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 nuclear factor kB (NF-kB) activation, resulting in dampened efficacy in vivo. However, we found that rapamycin, in addition to inhibiting the mammalian target of rapamycin (mTOR) pathway, facilitated autophagy and prevented p62 accumulation-induced NF-kB 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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U2 - 10.1126/scitranslmed.3010382
DO - 10.1126/scitranslmed.3010382
M3 - Article
C2 - 25411474
AN - SCOPUS:84911893167
SN - 1946-6234
VL - 6
JO - Science Translational Medicine
JF - Science Translational Medicine
IS - 263
M1 - 263ra161
ER -