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Researchers Discover NTRK1 Fusions as Potential PGx Marker in Lung Cancer


Originally published Oct. 29.

In a preliminary study, researchers have discovered that rearrangements in a gene called NTRK1 may drive lung cancer in a minority of patients. If confirmed in a larger trial, this marker will join the ever growing list of genetic aberrations that doctors can use to reclassify the lung cancer population into smaller and smaller patient subsets based on the unique molecular characteristics of their illness.

Researchers from a number of universities, Array Biopharma, and Foundation Medicine, published data in Nature Medicine from a study in which they tested 36 lung cancer patients by targeted next-generation sequencing and 56 lung cancer patients by fluorescence in situ hybridization and identified NTRK1 gene fusions in approximately 3 percent of study participants. These patients had lung adenocarcinomas, and based on standard testing did not have other known genetic alterations implicated with the disease, such as ALK fusions, EGFR mutations, ROS1 rearrangements, or other oncogenes RET, FGFR1, FGFR2, and FGFR3.

The NTRK1 gene endcodes for the TRKA protein, which is critical for the development and survival of nerve cells, particularly sensory neurons. The study authors propose that lung cancer patients with tumors characterized by this type of gene fusion can benefit from TRKA inhibitors. Array Biopharma, which participated in this study, is currently investigating ARRY-470 – an inhibitor of TRK receptors, TRKA, TRKB, and TRKC – as a pain reliever. Cephalon's lestaurtinib and Pfizer's non-small cell lung cancer drug Xalkori (crizotinib) also inhibit TRK receptors along with other receptors.

"Based on our data, clinical studies of selective TRKA inhibitors in NTRK1-rearranged NSCLC are warranted," wrote researchers in Nature Medicine led by University of Colorado's Robert Doebele.

In this study, when Doebele and his colleagues tested 36 patients using Foundation Medicine's targeted NGS test they identified two female never-smokers with NTRK1 gene fusions. In one woman the NTRK1 gene was fused with the MPRIP gene, which is implicated in another fusion gene in small-cell lung cancer. In the second patient, the NTRK1 gene was joined to the CD74 gene, which is known to fuse with the ROS1 oncogene.

The researchers confirmed the chromosomal rearrangements in the tumor cells of these patients through a FISH assay. Using this same assay, they then tested lung adenocarcinoma samples from 56 patients and identified an NTRK1 gene fusion in one additional sample. Due to the rarity of this marker in lung cancer patients, however, the researchers were unable to identify any NTRK1 gene fusions among the 230 lung adenocarcinoma samples in the Cancer Genome Atlas.

Doebele and his colleagues further probed whether NTRK1 gene fusions are oncogenic by expressing MPRIP-NTRK1 and CD74-NTRK1 in three non-cancer animal cell lines to observe the changes this would inspire. They found that the fusions did induce cancer-like activity in certain cell types.

The researchers then looked at how cancer patients' cells expressing MPRIP-NTRK1 and CD74-NTRK1 fusions reacted when treated with three different agents: Xalkori, currently marketed by Pfizer as a NSCLC treatment in patients with ALK rearrangements and given to patients in clinical trials with ROS1 positive tumors; Array Biopharma's investigational treatment ARRY-470; and Cephalon's investigational tyrosine kinase inhibitor lestaurtinib.

Doebele and his team reported in the paper that ARRY-470 and lestaurtinib exhibited the strongest activity by inhibiting autophosphorylation and proliferation of cells with NTRK1 fusions. Xalkori also had activity in these cell lines, but "less so" than the other two agents, they reported. "Crizotinib was a less potent inhibitor, although in a range similar to that seen for inhibition of EML4-ALK or SDC4-ROS1," Doebele and colleagues wrote in the paper. "The less potent effects of crizotinib on cell proliferation are consistent with decreased inhibition of phosphorylated TRKA and downstream phsophorylated ERK1/2."

Lestaurtinib and Xalkori inhibit TRK, in addition to a number of other kinases, while ARRY-470 only inhibits TRK. The level of efficacy of these drugs in cell lines, Doebele and his team observed, may be impacted by the specific kinases they inhibit.

The authors hypothesized that Xalkori's blockage of multiple kinases might be the reason for its lower potency against patients' tumor cells driven by NTRK1-fusions. By this theory, ARRY-470, inhibiting only TRK, may be a promising treatment for this lung cancer patient subset, although this has yet to be proven in larger clinical trials.

In the current study, ARRY-470 did not inhibit proliferation of cells expressing other cancer-driving genetic markers, such as ALK, EGFR, or ROS1, and didn't show activity in lung and colorectal cancer cell lines without NTRK1 fusions, the researchers pointed out.

This preliminary data sets the ground work for further exploring Xalkori, lestaurtinib, ARRY-470, and other TRK inhibitors in bigger clinical trials involving cancer patients with NTRK1 rearrangements. However, recruiting patients for such a trial may be challenging, if only around 3 percent of patients with lung adenocarcinomas harbor NTRK1 fusions.

Currently, around 35 percent of molecular markers associated with NSCLC are unknown. Among the known markers, EGFR and KRAS mutations are the most common, showing up in up to 30 percent and 25 percent of lung adenocarcinomas, respectively. In comparison, ROS1, ALK, and RET, rarely show up in NSCLC patients. The EML4-ALK fusion is associated with between 3 percent and 5 percent of NSCLC, while ROS1 rearrangements show up in between 1 percent and 2 percent of patients.

Because there were no studies involving TRKA inhibitors in lung cancer at the time Doebele and his team conducted their research, the patient with the MPRIP-NTRK1 fusion consented to off-label treatment with Xalkori. "The patient showed a minor radiographic response with a decrease in serum levels of tumor marker CA125 but experienced disease progression after [approximately] three months," Doebele and colleagues wrote in their paper. "This modest clinical activity of crizotinib is consistent with the in vitro activity that we observed and could be caused by non-TRKA kinase effects."

Cephalon and Array Biopharma are studying lestaurtinib and ARRY-470 in non-lung cancer indications. Cephalon has ongoing trials looking at lestaurtinib as a treatment against leukemias and lymphomas. Previously, researchers from Array Biopharma have presented data showing that ARRY-470 relieved pain in animal models of bone cancer but the agent also increased side effects, such as overeating and weight gain in mice.

Doebele and lead author Aria Vaishnavi from the University of Colorado were not available to comment for this article. Array Biopharma did not respond to an interview request to discuss the development plan for ARRY-470 ahead of press time.