👤 R Alejandro Marquez-Ortiz

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

Estrogen receptor positive (ER+) breast cancer (BC) represents a significant proportion of BC brain metastasis (BCBM) but remains understudied. Here, we report that FGFR1-amplification, a well-established driver of ER+ BC endocrine resistance, promotes ER+ BCBM colonization in young and aged mice, through brain-dependent mechanisms. FGFR1-dependent brain colonization in young and aged mice occurs via canonical FGF2/FGFR1 signaling and non-canonical NCAM1/FGFR1 interactions. Astrocytic FGF2-mediated paracrine activation of FGFR1 promoted BCBMs in estrogen-treated young mice, but FGF2 signaling decreased in the brain with aging and estrogen-depletion. Neuronal and glial NCAM1, which remain unchanged in young and aged brains, promoted adhesion to neurons and migration of ER+ BC cells, suggesting that interactions with astrocytes and neurons facilitate early ER+ BCBM colonization through FGFR1. Importantly, FDA-approved FGFR inhibitors effectively blocked early but not late metastatic progression only in young mice, suggesting limited efficacy of FGFR inhibitors to block non-kinase-dependent FGFR1 functions Show less