
==== Front
Neurooncol Adv
Neurooncol Adv
noa
Neuro-Oncology Advances
2632-2498
Oxford University Press US

10.1093/noajnl/vdae090.083
vdae090.083
Final Category: Novel Targets in CNS Metastases (Non-Immunologic)
AcademicSubjects/MED00300
AcademicSubjects/MED00310
NVTG-09 TARGETING TRKB IN LUNG-TO-BRAIN METASTATIC PROGRESSION
Contreras-Zárate Maria J University of Colorado, Denver/CO, USA

Koliavas Stella University of Colorado, Denver/CO, USA

Heasley Lynn University of Colorado, Denver/CO, USA

Pine Sharon University of Colorado, Denver/CO, USA

Nemenoff Raphael University of Colorado, Denver/CO, USA

Camidge D Ross University of Colorado, Denver/CO, USA

Cittelly Diana University of Colorado, Denver/CO, USA

8 2024
02 8 2024
02 8 2024
6 Suppl 1 2024 SNO/ASCO CNS Metastases Conference i25i25
© The Author(s) 2024. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.
2024
https://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

Abstract

Brain metastases (BM) are a common site of metastasis for both non-small cell (NSCLC) and small cell lung cancer, affecting 20-56% of advanced lung cancer (LC) patients. In breast cancer models, we have shown that astrocytes secrete brain-derived neurotrophic factor (BDNF), which, in a paracrine manner, activates its receptor tropomyosin-related kinase B (TrkB, also called NTRK2) in a subset of cancer cells, promoting BM. Although NTRK gene rearrangements are known to function as primary oncogenic drivers in a subset of NSCLC, wildtype TrkB has been shown to promote lung adenocarcinoma metastases and TrkB expression was associated with worse survival in multiple LC subtypes. Thus, we

HYPOTHESIZE

that paracrine BDNF/TRKB activation is also a mechanism whereby subsets of non-NTRK rearranged LC cells can colonize the brain. We investigated TrkB expression levels in murine (CMT167) and human (LU65, H358, PC9BR3, H2030BR3) LC cell lines and their ability to form BM in mouse models. TrkB expression varied among cell lines, with brain metastases incidence of 20% (CMT167), 50% (PC9BR3), 64% (H358) and 75% for H2030BR3. While all cells responded to BDNF stimulation activating AKT, ERK and PLCg signaling, H358 and H2030BR3 cells showed faster and stronger TRKB activation. Stimulation with astrocyte-conditioned media (Ast-CM) or coculture with astrocytes, activated TrkB and promoted proliferation and invasion of LC cells. Entrectinib, an FDA-approved drug for NTRK fusion-positive solid tumors, decreased BDNF and Ast-CM-induced TrkB activation and proliferation, particularly in models with increased BDNF-dependency. Importantly, co-culture of a subset of LC cells with astrocytes renders them less sensitive to Entrectinib, suggesting that additional survival mechanisms contribute to LC cell fitness in the brain niche. Ongoing studies interrogate the effectiveness of Entrectinib to decrease early and late brain metastatic progression in LC. These studies suggest that targeting TrkB could impact LC therapy even in tumors lacking NTRK rearrangements
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pmc
