Adding simvastatin to cetuximab enhances antitumor activity in KRAS-mutant colorectal (CRC) cancer cells, according to a study by Lee and colleagues in the Journal of the National Cancer Institute. The addition did not, however, enhance efficacy in BRAF-mutant cells.
At current, we have no effective treatment for metastatic CRC patients whose tumors harbor KRAS mutations and who have failed to respond to 5-fluorouracil combined with irinotecan or oxaliplatin chemotherapy. Statins such as simvastatin are 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors. As such, they decrease production of farnesyl pyrophosphate and geranylgeranyl pyrophosphate, which are essential substrates for posttranslational modifications of RAS and RAS homolog gene family, member A (RHOA). This suggests that statins may have antitumor effects in various cancers.
In this in vitro study, researchers found that simvastatin could overcome cetuximab resistance via modulation of BRAF activity and induced apoptosis by inducing the proapoptotic proteins BCL2L11 and BAD. This led them to conclude that the addition of simvastatin at a dose (40 mg–80 mg once daily) used in patients with cardiovascular disease may be an option for KRAS-mutant CRC patients, and to plan a phase 2 study (clinicaltrials.gov: NCT01281761).