ALK and ROS1 gene rearrangements known to drive subsets of lung cancer are also present in some colorectal cancers. These results imply that drugs used to target ALK and ROS1 in lung cancer may also have applications in this subset of colorectal cancer patients.
“When you have known oncogenes that are already targeted by FDA-approved drugs, it just made sense to look for these oncogenes in other cancers,” said Marileila Varella Garcia, PhD, from the Colorado University (CU) Cancer Center and the CU School of Medicine in Denver.
“By rethinking the way we understand cancers—as their genetic mutations and not just as the sites where they live in the body—we see that a therapy that targets a specific mutation may show benefit in treating any other cancer that shares the same mutation,” said Dara Aisner, MD, PhD, also from the CU Cancer Center.
In this study, published in Molecular Cancer Research (2013; doi:10.1158/1541-7786.MCR-13-0479-T), the researchers used fluorescence in situ hybridization to test for the oncogenic gene rearrangements in 236 tumor samples of colorectal cancer collected from patients enrolled in a large, Australian clinical trial. The work found one patient carrying the ALK rearrangement, confirming previous findings, and demonstrated the first finding of ROS1 as an oncogenic driver of colorectal cancer—in this case, in 2 of the 236 tumor samples.
Though the percentage of colorectal cancer patients with these gene arrangements is quite small, the researchers explained that the benefit to these few patients could be dramatic, and so it is worth the work to see if colorectal cancer patients can also benefit from drugs that are effective in lung cancer.
Surprisingly, these gene alterations tended to co-exist in colorectal tumors along with other molecular alterations—tumors that were positive for ALK rearrangements were also positive for the well-defined KRAS mutation; ROS1 mutations occurred in one specimen along with BRAF, a known oncogenic mutation.
“Conventional wisdom is that one molecular driver alteration exists throughout all tumor cells in a specimen, and that it’s mutually exclusive of other alterations. We found that neither of those axioms held true—some tumor regions had different alterations, and, even more surprisingly, in some regions, both alterations were seen. These findings show that you can find more than one alteration in a single specimen, and that not all cells within a single tumor are necessarily driven by the same oncogene,” Aisner said.
The group wrote that “identification of ALK and ROS1 oncogenes may open new therapeutic options for CRC [colorectal cancer],” specifically with the class of drugs known as tyrosine-kinase inhibitors (TKIs) shown to “turn off” ALK and ROS1 gene mutations thereby killing or slowing the growth of cancer cells. For example, the drug crizotinib was approved by the FDA in 2011 to treat ALK-positive lung cancer, and this drug or others that are in development to treat ALK+ and ROS1+ cancers may have similar benefit in CRC.