Dual treatment with lipophilic bisphosphonates and rapamycin inhibits KRAS-mutant lung tumor growth.
Major finding: Dual treatment with lipophilic bisphosphonates and rapamycin inhibits KRAS-mutant lung tumor growth.
Mechanism: Bisphosphonates impair KRAS prenylation and induce autophagy, which is enhanced by rapamycin.
Impact: Further clinical studies on this combination therapy in KRAS-driven lung cancer are warranted.
Efforts to directly target oncogenic KRAS, which is commonly mutated in many cancers including lung adenocarcinomas, have thus far been unsuccessful. An alternative strategy that has been proposed is to block the posttranslational prenylation of KRAS protein, which is required for its membrane localization and transforming activity; however, these inhibitors have thus far not been effective in clinical trials. In addition, bisphosphonates such as zoledronate have been shown to impair the synthesis of lipid substrates required for prenylation via inhibition of farnesyldiphosphate synthase (FPPS) and geranylgeranyldiphosphate synthase (GGPPS). Xia and colleagues found that the lipophilic bisphosphonate BPH-1222, a zoledronate analogue that targets both FPPS and GGPPS, effectively suppressed the growth of KRAS-mutant lung cancer cell lines and induced cell death. Consistent with the increased sensitivity of KRAS-mutant cells to BPH-1222, treatment with this compound impaired KRAS prenylation, resulting in decreased GTP-bound active KRAS, increased KRAS degradation, and reduced downstream AKT signaling. In addition, BPH-1222–mediated blockade of protein prenylation triggered the endoplasmic reticulum stress response and induced autophagy, suggesting that the addition of autophagy inhibitors might enhance the sensitivity of KRAS-mutant cells to BPH-1222. However, although dual treatment with BPH-1222 and the autophagy inhibitor chloroquine decreased lung cancer cell growth in vitro, this combination did not inhibit KRAS-mutant tumor growth in vivo due to accumulation of p62 and activation of proproliferative NFκB signaling. In contrast, combined treatment with BPH-1222 and the autophagy inducer rapamycin inhibited mTOR activity and prevented NFκB-driven proliferation, resulting in suppression of KRAS-induced tumor growth and prolonged mouse survival in multiple lung cancer models. These findings support additional clinical investigation of the combination of lipophilic bisphosphonates and rapamycin for the treatment of KRAS-mutant lung adenocarcinomas.