FRESH SCIENCE for Clinicians

News about basic science of interest and relevance for cancer clinicians

Tuesday, February 14, 2012

New Oncogenic Driver Identified in Lung Adenocarcinomas

Mutations in the RET (REarranged during Transfection) gene have already been associated with thyroid cancers. This week, three research groups reported online in Nature Medicine that RET gene fusions may be drivers in 1-2% of lung adenocarcinomas.


Although the absolute percentage of RET-driven tumors is small, the clinical benefits may be significant, in the same way that EML4-ALK gene fusions, which occur in fewer than 5% of non-small cell lung cancer patients, have been important.


That is, the new results will be important if – and this remains a big “if” – the RET-fusion tumors respond to RET inhibitors. In vitro data showed the RET-driven cancer cells did respond to small molecule RET inhibitors. The catch, of course, is that the same may or may not be true in patients.


The good news, though, is that several FDA-approved tyrosine kinase inhibitors, including sorafenib, sunitinib, and vandetanib, block RET activity. Therefore, testing the hypothesis in patients should be relatively straightforward.


The evidence that the RET gene fusions are driving the cancers is pretty good. All three teams noted that the RET gene fusions, which most frequently linked RET coding sequence with that of the kinesin family 5B gene (KIF5B), occurred in the absence of other known lung cancer drivers, such as alterations in EGFR, KRAS, ALK, and HER2. That mutual exclusivity indicates that the RET fusions function as drivers, rather than passengers.


Interestingly, the three groups used a wide mix of techniques to identify the rare alteration. In a project led by researchers at the Dana-Farber Cancer Institute in Boston and a company called Foundation Medicine in Cambridge, the team used next-generation sequencing to analyze 145 cancer-related genes in 40 colorectal and 24 non-small cell lung cancers. After discovering a KIF5B-RET fusion in one lung tumor, the researchers used RT-PCR to test an additional 526 tumors and found 10 more RET fusion-positive tumors.


Meanwhile, investigators at the National Cancer Center Research Institute in Tokyo used whole-transcriptome sequencing to look for gene fusions in 30 lung adenocarcinomas. After finding one KIF5B-RET fusion, they used RT-PCR and Sanger sequencing to analyze 319 additional tumors and uncovered six more (1.9%) that carried KIF5B-RET fusions.


Finally, investigators at the Japanese Foundation for Cancer Research in Tokyo used a mix of immunohistochemistry and fluorescent in situ hybridization (FISH) to look for abnormal gene fusions. During the FISH experiments, they tested a probe for KIF5B, because it has been shown previously to fuse to ALK in rare cases. They too uncovered KIF5B-RET fusions. Additionally, they noted that one RET fusion was discovered during a routine histopathological diagnosis; a tumor that showed a mucinous cribriform pattern, which is often associated with ALK fusions, instead carried a RET fusion.


Regardless of the specific methods used to uncover the RET fusions, it appears that researchers are chipping away at the percentage of non-small cell lung cancers that lack a known driver. In fact, the Dana-Farber–Foundation Medicine team report that the RET fusions accounted for 6.3% (10 out of 159) of the tumors analyzed that lacked a known driver.


If the RET inhibitors are clinically active in these patients, that means 6.3% more patients can have personalized cancer care –– and that will be a good thing.