Frequent mutations in the neurotrophic tyrosine receptor kinase gene family in large cell neuroendocrine carcinoma of the lung

Abstract

The neurotrophic tyrosine receptor kinase (NTRK) family is potentially implicated in tumorigenesis and progression of several neoplastic diseases, including lung cancer. We investigated a large number of pulmonary neuroendocrine tumors (PNETs) and non-small cell lung carcinomas (NSCLCs) without morphological evidence of neuroendocrine differentiation for mutations in the NTRK gene family. A total of 538 primary lung carcinomas, including 17 typical carcinoids (TCs), 10 atypical carcinoids (ACs), 39 small cell lung carcinomas (SCLCs), 29 large cell neuroendocrine carcinomas (LCNECs), and 443 NSCLCs were evaluated by single-strand conformation polymorphism (SSCP) and sequencing of the tyrosine kinase domain (TKD) of NTRK1, NTRK2, and NTRK3. The NTRK1 gene was never found to be mutated. A total of 10 somatic mutations were detected in NTRK2 and NTRK3, mostly located in the activating and catalytic loops. NTRK mutations were seen in 9 (10%) out of 95 PNETs but in 0 out of 443 NSCLCs investigated. No mutations were observed in TCs, ACs, and SCLCs. Interestingly, all the mutations were restricted to the LCNEC histotype, in which they accounted for 31% of cases. A mutational analysis, performed after microdissection of LCNECs combined with adenocarcinoma (ADC), showed that only neuroendocrine areas were positive, suggesting that NTRK mutations are involved in the genesis of the neuroendocrine component of combined LCNECs. Our data indicate that somatic mutations in the TKD of NTRK genes are frequent in LCNECs. Such mutational events could represent an important step in the cancerogenesis of these tumors and may have potential implications for the selection of patients for targeted therapy.

Investigation of neurotrophic tyrosine kinase receptor 1 fusions and neurotrophic tyrosine kinase receptor family expression in non-small-cell lung cancer and sensitivity to AZD7451 in vitro

“…Both the myosin phosphatase Rho-interacting protein (MPRIP)-NTRK1 and CD74-NTRK1 fusions lead to constitutive TRKA kinase activity and have been shown to be oncogenic. In addition, Marchetti et al (7) demonstrated that there are NTRK3 mutations associated with the TRKC receptor and NTRK2 mutations encoding the NTRK2 (TRKB) receptor in lung large-cell neuroendocrine carcinoma (LCNEC). Recently, the TRKB signaling pathway was also reported to be a potential therapeutic target for lung LCNEC (8).…”

Long-term Survival of Large Cell Neuroendocrine Lung Carcinoma with Bony Metastases: A Case of Immunoprotectivity?

“…Multiple series have reported 85-98% of patients who had a surgical resection of LCNEC had a history of habitual cigarette smoking [1,2]. Genetic risk factors include mutation of the epidermal growth factor receptor (EGFR) gene or tyrosine kinase domain (TKD) of the neurotrophic tyrosine receptor kinase (NTRK) gene [3,4]. LCNEC can be a challenge to diagnose since patients rarely present with pulmonary symptoms and <20% present with cough or hemoptysis [2,5].…”

Identification and preclinical characterization of AZ-23, a novel, selective, and orally bioavailable inhibitor of the Trk kinase pathway

“…Activating genetic translocations involving the linkage of NTRK1 and NTRK3 to various partner proteins have been described in several cancers, most notably in thyroid and secretory breast carcinomas. A growing list of intriguing point mutations in the Trk genes have also been recently reported in primary tumors of various origin (5,6). Whereas the functional consequences of these mutations have yet to be elucidated in most cases, the localization of many of the mutations to key residues of the kinase domain suggests that they could be activating in nature.…”

“…Trk receptors have also been shown to be potent oncogenes with roles in malignant transformation, metastasis, and survival signaling in human tumors (3)(4)(5). Independent mechanisms of Trk pathway activation, including constitutive oncogenic fusions, autocrine signaling, and point mutations, have been described in medulloblastoma; neuroblastoma; acute myelogenous leukemia (AML); and thyroid, pancreatic, breast, lung, and prostate cancers, suggesting that the Trk pathway may be more broadly involved in carcinogenesis and tumor cell survival (6)(7)(8)(9)(10)(11)(12).…”