Newly identified fusion genes in lung and colorectal cancer may guide treatment with 'targeted' drugs

The genetic alterations -- pieces of two genes fused together -- showed up in a massive search of the DNA in stored tumor samples of non-small cell lung cancer and colorectal cancer, said researchers from Dana-Farber Cancer Institute and Foundation Medicine, Inc. These specific genetic abnormalities had not been previously linked to the two cancer types.

Their results were published online by the journal Nature Medicine. Other cancers with similar genetic alterations often respond to "targeted" drugs s that block overactive proteins called tyrosine kinase inhibitors. This suggests that the same drugs also may be effective against lung and colorectal tumors driven by the newly found gene fusions. Because these drugs are already approved to treat cancer, it should be possible to move rapidly to clinical trials in colorectal and lung cancer, the authors said.

If the trials are successful, physicians could potentially test patients' tumors for the presence of the gene fusions and prescribe a medication matched to those alterations, said Pasi A. Jänne, MD, PhD, a thoracic oncologist at Dana-Farber and co-senior author of the report along with Philip J. Stephens, PhD, and Maureen Cronin, PhD, of Foundation Medicine. Doron Lipson, PhD, is the paper's first author. "This is a textbook example of personalized medicine for lung cancer -- a genetic alteration found in a subset of patients that we can now look for and use as a means to select particular therapies," Jänne said.

"In the past, although these targeted drugs were available, they were not chosen for a particular subset, but instead given to everybody," he explained. "This will increase the likelihood of those therapies being more successful."

The researchers estimate that less than 1 percent of Caucasians and about 2 percent of Asians with lung cancers carry this alteration -- a fusion gene labeled KIF5B-RET. However, they said the finding opens a significant therapeutic opportunity.

"In a common indication like non-small cell lung cancer, identifying even a small subpopulation of individuals with gene fusions who may be responsive to a targeted therapy has the potential for major therapeutic impact," said Stephens, executive director of cancer genomics at Foundation Medicine. "This joint research with Dana-Farber translates genomic research to the clinic and we expect that it may quickly have a positive impact for patients."

The American Cancer Society projects that 226,160 Americans will be diagnosed with lung cancer in 2012 and 160,340 will die of the disease.

Foundation Medicine scientists identified the novel fusion gene in a DNA tumor sample removed from a 44-year-old man with non-small cell lung cancer (NSCLC) who had never smoked. The hybrid gene is composed of a piece of a cell growth gene, RET, and part of another gene, KIF5B. This abnormal gene combination causes RET to act like a growth switch stuck in the "on" position, spurring uncontrolled cell division.

The company formed a collaboration with Jänne and his Dana-Farber colleagues to follow up the discovery. "We looked for the RET fusion gene in a larger collection of lung tumor samples to determine how common it is, and if it is acting as an oncogene [a gene that drives cancer]" said Jänne. They searched samples from 121 Caucasian patients and 405 Asian patients who had never smoked or had rarely smoked in the past. The RET fusion gene was detected in 1 of the Caucasian samples (0.8 percent) and 9 of the Asian patient samples (2 percent).

Thyroid cancers containing RET gene hybrids are known to respond to certain targeted drugs that inhibit RET. When Dana-Farber investigators tested three such inhibitors -- sorafenib, sunitinib and vandetinib -- on cultured cells containing the newly discovered RET mutation, each of the drugs killed those cells, the scientists reported. Jänne noted that some patients with NSCLC have responded to treatment with these inhibitor drugs. The researchers want to find out whether those patients had RET mutations in their tumors.

The Foundation Medicine scientists also sequenced DNA samples from 40 patients with colorectal cancer. Along with numerous known mutations, the researchers identified a novel gene alteration, C2orf44-ALK, that causes a 90-fold overexpression of the ALK protein leading to cancerous proliferation. Overexpressed ALK is also found in a small percentage of lung cancer cases and can be inhibited by the targeted drug crizotinib. This raises the possibility of using crizotinib to target the C2orf44-ALK fusion gene in colorectal cancer, the researchers said.

In addition to Cronin, Jänne, Lipson and Stephens, the paper's co-authors were from Sharett Institute of Oncology, Jerusalem; TEVA Pharmaceutical Industries, Petach Tikva, Israel; Samsung Medical Center, Seoul, Korea; Nagoya City University Graduate School of Medical Sciences, Japan; Asan Medical Center, Seoul, Korea; and Albany Medical Center, New York.

The research was funded in part by the Dana-Farber/Harvard Cancer Center Lung Cancer SPORE grant from the National Cancer Institute and the Cammarata Family Foundation Research Fund.