Abstract IA41: A new TRacK in lung cancer: NTRK1 gene fusions as a therapeutic target.

Non-small cell lung cancer (NSCLC) is a heterogeneous disease that can be organized into groups designated by the dominant oncogene or oncogenic ‘driver’. Classification of NSCLC by oncogenes is critical because oral kinase inhibitors or other targeted therapeutic strategies can often effectively inhibit these oncogenes leading to dramatic tumor shrinkage and thus significant clinical benefit for patients. Several of these oncogenes are the result of chromosomal translocations that generate gene fusions in which the kinase domain of a receptor tyrosine kinase is aberrantly expressed and activated by the addition of sequence from an unrelated gene. Recent examples of such gene fusions in NSCLC include those involving the ALK, ROS1, RET and FGFR1/2/3 genes. We have recently discovered previously uncharacterized gene fusions involving the NTRK1 gene in patients with lung adenocarcinoma whose tumors did not harbor other known oncogenes. These novel oncogenes contain the 3 portion of the neurotrophic tyrosine kinase, receptor, type 1 (NTRK1) gene, which encodes the kinase domain of the TRKA receptor. Cloning and ectopic expression of these novels genes in non-tumor cells demonstrate their oncogenic potential. Treatment of cells expressing NTRK1 gene fusions with TRK inhibitors inhibits autophosphorylation of the chimeric TRKA proteins, important downstream signaling pathways, and cellular proliferation. Gene fusions involving NTRK1 (TRKA), NTRK2 (TRKB), and NTRK3 (and TRKC) have now been identified across multiple tumor types. As clinical next generation sequencing becomes increasingly common, cancer patients with these somatic gene abnormalities will be identified and therefore it is critical to understand their biology, utility as a therapeutic target, and mechanisms of intrinsic and acquired drug resistance in order to advance a precision medicine strategy for the treatment of NSCLC.

Citation Format: Robert C. Doebele. A new TRacK in lung cancer: NTRK1 gene fusions as a therapeutic target. [abstract]. In: Proceedings of the AACR-IASLC Joint Conference on Molecular Origins of Lung Cancer; 2014 Jan 6-9; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2014;20(2Suppl):Abstract nr IA41.