A certain type of mutation in a protein, called RET, occurs in a significant subset of lung cancer patients, a recent study shows. Known as ‘rearrangements,’ these mutations fuse the RET gene with other nearby genes, resulting in a RET protein that contains parts of other proteins and is hyperactive. Patients with similar rearrangement mutations in another gene, ALK, can experience drastic improvements from treatment with ALK inhibitors such as crizotinib (Xalkori). This raises the hope that patients with RET rearrangement mutations may be similarly helped by drugs that block RET–either novel RET inhibitors or existing tyrosine kinase inhibitors (TKIs), such as vandetanib (Caprelsa), sunitinib (Sutent), sorafenib (Nexavar), or ponatinib (Iclusig). Identifying patients who may benefit from such treatments would be made easier by the new test for RET mutations developed by the study’s authors. When examining a group of patients with lung adenocarcinoma, a type of non-small cell lung cancer (NSCLC), who did not have mutations in other cancer-relevant genes, the researchers found that 15% had RET rearrangement mutations.
The leukemia drug ponatinib (Iclusig) also appears to target mutant versions of two proteins involved in non-small cell lung cancer (NSCLC). This is supported by two recent studies in which Iclusig slowed the growth of cells with mutant RET and FGFR proteins. The drug also shrank tumors with RET mutations that had been grown in mice. Based on these findings, Iclusig manufacturer ARIAD Pharmaceuticals is planning a phase II clinical trial to investigate the drug’s effectiveness against NSCLC with RET mutations. A phase II trial assessing Iclusig’s effects in squamous cell carcinoma (SCC) of the lung with FGFR mutations is already underway at the Dana-Farber Cancer Institute, Boston, Massachusetts, and is currently enrolling participants.
“ARIAD Pharmaceuticals, Inc. (NASDAQ: ARIA) today announced the presentation of preclinical data on ponatinib (Iclusig™) , at the American Association for Cancer Research (AACR) Annual Meeting 2013, in Washington. In separate studies, ponatinib is shown to potently inhibit RET, a clinically proven oncogenic driver of medullary thyroid cancer (MTC) and non-small cell lung cancer (NSCLC), and FGFR, which is commonly mutated in endometrial, lung and other cancers…”