Abstract
Gene fusions involving NTRK1 (which encodes TRKA) were identified in 3.3% of patients with NSCLC.
Major finding: Gene fusions involving NTRK1 (which encodes TRKA) were identified in 3.3% of patients with NSCLC.
Concept: TRKA inhibitors block TRKA autophosphorylation and proliferation in cells expressing NTRK1 fusions.
Impact: Patients with NTRK1-rearranged NSCLC may benefit from treatment with TRKA-selective inhibitors.
Selective kinase inhibitors have shown activity in a subset of patients with non–small cell lung cancers (NSCLC) that harbor activating mutations or rearrangements in EGFR, ALK, ROS1, and RET, but many patients with NSCLC lack these genetic alterations and are not candidates for the corresponding targeted therapies. Vaishnavi and colleagues performed next-generation sequencing on 36 NSCLCs without mutations in genes known to be mutated or rearranged in lung cancer and found two in-frame fusion events involving the kinase domain of neurotrophic tyrosine kinase receptor type 1 (NTRK1), which encodes the nerve growth factor receptor transforming tyrosine kinase protein A (TRKA). NTRK1 was fused to myosin phosphatase Rho interacting protein (MPRIP) in one case and the major histocompatibility complex class II invariant chain gene, CD74, in another. A third fusion involving NTRK1 and an unknown locus was identified among 56 additional NSCLCs by fluorescent in situ hybridization, for an overall frequency of 3.3%. Forced expression of MPRIP–NTRK1 and CD74–NTRK1 led to TRKA autophosphorylation and induced cytokine-independent growth, anchorage-independent growth, and tumor formation in nude mice, suggesting that these fusions are oncogenic. Treatment of NTRK1 fusion-expressing cells with the TRKA-selective inhibitor ARRY-470 or less specific inhibitors such as lestaurtinib or crizotinib blocked TRKA autophosphorylation, suppressed proliferation, and inhibited colony formation in soft agar. Based on these findings, the patient with the MPRIP–NTRK1 fusion, for whom no standard therapies were available, was treated with crizotinib. The patient experienced a minor radiologic response although her disease progressed after approximately 3 months. These results provide a rationale for clinical evaluation of TRKA-selective inhibitors for NTRK1-rearranged NSCLC.
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