title: A combination therapy for KRAS-driven lung adenocarcinomas using lipophilic bisphosphonates and rapamycin.
abstract: 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 κB (NF-κB) 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-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.
authors.affiliation: Laboratory of Genetics, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors.forename: Yifeng
authors.initials: Y
authors.lastname: Xia
authors.affiliation: Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
authors.forename: Yi-Liang
authors.initials: YL
authors.lastname: Liu
authors.affiliation: Department of Pharmacology & Pharmaceutical Sciences, School of Medicine, Tsinghua University, Beijing 100084, P.R. China.
authors.forename: Yonghua
authors.initials: Y
authors.lastname: Xie
authors.affiliation: Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhu
authors.affiliation: Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
authors.forename: Francisco
authors.initials: F
authors.lastname: Guerra
authors.affiliation: Laboratory of Genetics, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors.forename: Shen
authors.initials: S
authors.lastname: Shen
authors.affiliation: Laboratory of Genetics, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors.forename: Narayana
authors.initials: N
authors.lastname: Yeddula
authors.affiliation: Clayton Foundation Laboratories for Peptide Biology, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Fischer
authors.affiliation: Clayton Foundation Laboratories for Peptide Biology, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors.forename: William
authors.initials: W
authors.lastname: Low
authors.affiliation: Department of Pharmacology & Pharmaceutical Sciences, School of Medicine, Tsinghua University, Beijing 100084, P.R. China.
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Department of Pharmacology & Pharmaceutical Sciences, School of Medicine, Tsinghua University, Beijing 100084, P.R. China. Collaborative Innovation Center for Biotherapy, Tsinghua University, Beijing 100084, P.R. China. Collaborative Innovation Center for Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, P.R. China. verma@salk.edu eoldfiel@illinois.edu zhangyonghui@tsinghua.edu.cn.
authors.forename: Yonghui
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA. Center for Biophysics and Computational Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA. verma@salk.edu eoldfiel@illinois.edu zhangyonghui@tsinghua.edu.cn.
authors.forename: Eric
authors.initials: E
authors.lastname: Oldfield
authors.affiliation: Laboratory of Genetics, Salk Institute for Biological Studies, La Jolla, CA 92037, USA. verma@salk.edu eoldfiel@illinois.edu zhangyonghui@tsinghua.edu.cn.
authors.forename: Inder M
authors.initials: IM
authors.lastname: Verma
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000473:pathology; D000818:Animals; D004164:Diphosphonates / Q000008:administration & dosage / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D011905:Genes, ras; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D020123:Sirolimus / Q000008:administration & dosage / Q000627:therapeutic use*
chemical_list: D004164:Diphosphonates; D020123:Sirolimus