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. Copyright © 2014, American Association for the Advancement of Science.