Targeting Wild-type NTRK in NTRK Fusion-Negative Lung Cancer Decreases Brain Metastases

The central nervous system (CNS) is a common site of metastasis for both non-small cell and small cell lung cancer, yet the therapeutic strategies to prevent and decrease lung cancer brain metastases (BM) remain limited. Tyrosine kinase inhibitors have shown promising results in increasing overall response in BM, owing to their brain penetrance and increased effectiveness; however, their use is limited to a small group of tumors carrying specific oncogenic drivers. Among these, inhibitors targeting neurotrophic tyrosine receptor kinases (NTRK) are showing promising effects in reducing CNS metastases in cancers driven by gene rearrangements of these drugs' targets. However, wild-type NTRKs are susceptible to activation by their canonical ligands, which are expressed throughout the BM niche and can, in a paracrine manner, activate NTRK function in cancer cells. In this study, we show that NTRKs are expressed in primary tumors, BM, and lung cancer cells with various driver mutations expressing wild-type NTRK2 (WT-TrkB). We demonstrate that WT-TrkB activates downstream signaling and proliferation in response to exogenous brain-derived neurotrophic factor (BDNF) and conditioned media from reactive astrocytes known to secrete BDNF in the brain niche. Importantly, the FDA-approved NTRK inhibitor entrectinib blocked BDNF and astrocyte-induced survival pathways in multiple lung cancer cell lines, decreased their proliferation in vitro, and effectively prevented BM colonization and progression in vivo without significant effects on extracranial disease. Thus, these studies suggest that brain-dependent activation of NTRK is critical for BM of WT-NTRK+ lung cancers; therefore, NTRK inhibitors can be used to target nonfusion NTRK function to prevent or decrease BM.

These studies demonstrate that NTRK wild-type receptors are important drivers of brain metastatic colonization and progression in different subtypes of lung cancer, independent of their driver alterations. Thus, they provide a rationale to expand the use of FDA-approved NTRK inhibitors with brain penetrance for the prevention of CNS metastases.