KRAS-mutant lung adenocarcinoma has not been successfully targeted therapeutically. In a study reported in Science Translational Medicine, Xia and colleagues found that the combination of lipophilic bisphosphonates and rapamycin exhibited promising activity in this setting.
Lipophilic bisphosphonates inhibit farnesyl and geranylgeranyl diphosphate synthases, inhibiting prenylation of KRAS and other small G proteins (heterotrimeric GTP-binding protein, heterotrimeric guanine nucleotide-binding proteins) important to tumor growth and cell survival. Rapamycin is an mTOR inhibitor. Bisphosphonate treatment of tumor cells induced autophagy but subsequently led to p62 accumulation and consequent NF-κB activation, yielding little efficacy in the KRAS G12D mouse lung model. In addition to inhibiting the mTOR pathway, rapamycin induced autophagy and prevented p62 accumulation-induced NF-κB activation and tumor cell proliferation. The combination showed far greater efficacy in the KRAS G12D model than either agent alone.
The investigators concluded: “Overall, these results suggest that using lipophilic bisphosphonates in combination with rapamycin may provide an effective strategy for targeting lung adenocarcinomas harboring KRAS mutations.” ■
Xia Y, et al: Sci Transl Med 6:263ra161, 2014.