AURORA, Colo. - A study led by scientists at University of Colorado Cancer Center and Dana-Farber Cancer Institute in Boston has uncovered a new sub-type of lung cancer. The study revealed a gene fusion -- a forced merger of two normally separate genes – that spurs the cells to divide rapidly causing non-small cell lung cancer. The study is published in the journal Nature Medicine.
Scientists from the CU Cancer Center and Dana-Farber collaborated on the finding. The group went a step beyond identifying the gene mutation, NTRK1, that drives some lung cancers. The scientists also showed the abnormal cells can be targeted by several drugs.
“Whether a drug already is in clinical trials, or already approved for another cancer, or just sitting on the pharma shelf somewhere, many drugs exist that turn off these candidate genes," said Robert C. Doebele, MD, PhD (pictured above), the study’s senior author and investigator at the CU Cancer Center.
Doebele found Array BioPharma in Boulder, Colo. happened to have several compounds specific to NTRK1. The group showed that mutated NRTK1 genes in cells treated with drug candidate ARRY-470 and others was effectively turned off. The drug blocks a protein causing cancer cells to die.
“This is still preclinical work," Doebele said, "but it's the first – and maybe even second and third – important step toward picking off another subset of lung cancer with a treatment targeted to the disease's specific genetic weaknesses."
Foundation Medicine, Inc. performed next-generation DNA sequencing tests – which read the individual elements of the genetic code over long stretches of chromosomes – on tumor samples from 36 patients with lung adenocarcinomas whose tumors did not contain any previously known genetic alterations that could be found with standard clinical tests. In two of those samples – both from women who had never smoked – investigators found that a key region of the NTRK1 gene had become fused to normally distant genes (to the gene MPRIP in one patient; and the gene CD74 in the other).
NTRK1 holds the blueprint for a protein called TRKA, which dangles from the surface of cells and receives growth signals from other cells. The joining of NTRK1 to other genes causes TRKA to issue cell-growth orders on its own, without being prompted by outside signals.
In the laboratory, investigators mixed NTRK1-inhibiting agents into lung adenocarcinoma cells harboring NTRK1 fusions. The result was a dampening of TRKA’s activity and the death of the cancer cells.
Leila Varella-Garcia, PhD, at the CU Cancer Center then designed a new test using fluorescence in situ hybridization (FISH) to detect NTRK1 fusions and tested an additional 56 tumor samples. Three of 91 tumor samples, which had no other sign of cancer-causing genetic abnormalities, had fusions involving NTRK1.
“These findings suggest that in a few percent of lung adenocarcinoma patients – people in whose cancer cells we had previously been able to find no genetic abnormality – tumor growth is driven by a fusion involving NTRK1,” said Pasi A. Jänne, MD, PhD, of Dana-Farber, the senior co-author of the paper. “Given that lung cancer is a common cancer, even a few percent is significant and translates into a large number of patients.”
The co-lead authors of the study are Aria Vaishnavi, BS, of the University of Colorado School of Medicine and Marzia Capelletti, PhD, of Dana-Farber. Co-authors include Anh Le, BA, Severine Kako, Sakshi Mahale, MS, Kurtis Davies, PhD, Dara Aisner, MD, PhD, Amanda Pilling, PhD Eamon Berge, MD, and Marileila Varella-Garcia, PhD, of the University of Colorado School of Medicine; Mohit Butaney, Dalia Ercan, and Peter Hammerman, MD, PhD, of Dana-Farber; Levi Garraway, MD, PhD, of Dana-Farber and the Broad Institute of MIT and Harvard; Gregory Kryukov, PhD, of the Broad Institute; Jhingook Kim, MD, of Samsung Medical Center, Seoul, Korea; Hidefumi Sasaki, MD, of Nagoya City University, Nagoya, Japan; Seung-il Park, MD, PhD, of Asan Medical Center, Seoul, Korea; Julia Haas, PhD, and Steven Andrews, PhD, of Array BioPharma; Doron Lipson, PhD, Philip Stephens, PhD, and Vince Miller, MD, of Foundation Medicine.
The research was supported by the Colorado Bioscience Discovery Evaluation Grant Program, the National Institutes of Health, and the Boettcher Foundation’s Webb-Waring Biomedical Research Program, the Cammarata Family Foundation Research Fund, and the Nirenberg Fellowship at Dana-Farber.