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 tr

SUBMITTER: Xia Y 

PROVIDER: S-EPMC4326221 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature