85 percent of the lung cancer cases are of the non-small-cell lung carcinoma (NSCLC) type which is not sensitive to chemotherapy. Hence, NSCLC therapies are usually based on drug treatment. A commonly used drug for the treatment of NSCLC is alectinib which acts on the gene rearrangement known as ALK. ALK rearrangement is seen in 3 to 5 percent of NSCLC patients.
Alectinib belongs to a class of drugs known as ALK tyrosine kinase inhibitors. In 25 percent of the patients, secondary cancer mutations are observed which can lead to poor outcomes of alectinib in ALK-NSCLC patients.
The researchers have found that secondary cancer mutations can reduce the effectiveness of alectinib, however, they have also suggested ways to overcome this issue.
On analysis, it was seen that the cancer's progression-free survival was significantly poor in patients with TP53 mutations who received alectinib treatment. Similar conclusion was seen for treatment with other ALK tyrosine kinase inhibitors.
p53 proteins are a set of proteins that play a role in preventing cancer formation. Resistance to drugs develops due to the loss of normal p53 function in ALK-rearranged NSCLC.
Investigations were conducted on how to overcome the adverse effect of alectinib when secondary TP53 mutations occur. According to the biochemical mechanisms, the researchers have proposed to combine alectinib with another drug: ixazomib. Ixazomib belongs to the class of proteasome inhibitors that block the action of proteasomes, which in turn break down proteins.
Experiments conducted in mice showed general tumor shrinkage, and complete decrease in size and severity of 3 out of 8 tumors.
The researchers showed that the combined use of alectinib and a proteasome inhibitor can restore alectinib efficacy in treating ALK-rearranged NSCLC. Clinical trials are required to validate this combination therapy.