The central nervous system (CNS) is a common site of metastatic spread for both non-small cell and small cell lung cancer, yet the therapeutic strategies to prevent and decrease lung cancer brain meta Show more
The central nervous system (CNS) is a common site of metastatic spread for both non-small cell and small cell lung cancer, yet the therapeutic strategies to prevent and decrease lung cancer brain metastases remain limited. Tyrosine kinase inhibitors have shown promising results in increasing the overall response in brain metastases, owing to their brain penetrance and increased effectiveness; however, their use is limited to the small group of tumors carrying specific oncogenic drivers. Among these, inhibitors with activity against neurotrophic tyrosine receptor kinases (NTRKs) 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 brain metastatic niche and can, in a paracrine manner, activate NTRK function in cancer cells. Here we show that NTRKs are expressed in primary tumors, brain metastases, 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 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 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 rationale to expand the use of FDA-approved NTRK inhibitors with brain penetrance for the prevention of CNS metastases. Show less
Lung cancer remains a leading cause of cancer-related mortality worldwide. Depression, highly prevalent in lung cancer patients, not only impairs quality of life but also adversely affects disease pro Show more
Lung cancer remains a leading cause of cancer-related mortality worldwide. Depression, highly prevalent in lung cancer patients, not only impairs quality of life but also adversely affects disease progression and treatment outcomes through complex biological pathways. Previously considered merely a psychological reaction, depression is now recognized as sharing bidirectional pathophysiological interactions with lung cancer. This narrative review comprehensively reviews current evidence on the molecular mechanisms linking depression to lung cancer progression, with a focus on dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis and sympathetic nervous system (SNS), cytokine-mediated inflammation, and the lung-brain axis involving BDNF/TrkB signaling. We also discuss the potential therapeutic implications of antidepressants, including their effects on apoptosis, autophagy, and immune modulation. Key findings suggest that depression promotes tumor progression via chronic stress pathways, while antidepressants may counter these effects through multiple mechanisms. Understanding these pathways may inform integrated treatment strategies and improve prognosis in lung cancer with comorbid depression. Show less