Combining Proteasome Inhibitor and Alectinib Shows Promise for Treating NSCLC

A research team from Kanazawa University have found that secondary cancer mutations reduce the efficacy of Alectinib, a commonly used drug for non-small-cell lung carcinoma treatment (NSCLC). In their study—published in Clinical Cancer Research—they also address how to overcome the issue.

The researchers looked at data on 124 NSCLC patients who were treated with ALK tyrosine kinase inhibitors, including alectinib, and who had tested positive for the ALK gene rearrangement. Out of these, for 31 patients, a secondary gene rearrangement known as TP53 mutation was detected. Lead researcher Azusa Tanimoto and his colleagues looked at the correlation between the use of alectinib and TP53 mutations in this group of patients.

The data showed that the cancer's progression-free survival was significantly poorer in patients with TP53 mutations who received alectinib treatment. (The same conclusion was obtained for other treatments with other ALK tyrosine kinase inhibitors.) The resistance to the drugs is linked to the loss of normal p53 function in ALK-rearranged NSCLC; p53 refers to a set of proteins that are known to play a role in preventing cancer formation.

The scientists then investigated how to overcome the adverse effect of alectinib when secondary TP53 mutations occur. Based on their insights into the biochemical mechanisms at play, they proposed to combine alectinib with another drug: ixazomib. The latter is a drug from the class of proteasome inhibitors, which block the action of proteasomes, which in turn break down proteins. Experiments in mice showed promising results: general tumor shrinkage, and complete regression of 3 out of 8 tumors.