NIH grant: Establishing pre-clinical models of osimertinib resistance-mediated brain metastasis (1R03OD039968-01)

retained text

NIH grant 1R03OD039968-01: Establishing pre-clinical models of osimertinib resistance-mediated brain metastasis
Institute: {'code': 'OD', 'abbreviation': 'OD', 'name': 'NIH Office of the Director', 'admin_org_id': '12500055', 'admin_funding_url': ''}. PI: Hiromi Inoue Wettersten. Award: $120000.
Start: 2026-07-01T00:00:00.
PROJECT SUMMARY/ABSTRACT
 Osimertinib is a third-generation epidermal growth factor receptor (EGFR) inhibitor and the preferred treatment
for both early- and late-stage non-small cell lung cancer (NSCLC). However, resistance to this therapy inevitably
develops, often leading to new brain metastases. Research on resistance mechanisms has primarily focused on
identifying mutations in patient samples. These mutations vary across tumor sites, highlighting the heterogeneity
of cellular responses to osimertinib. Furthermore, many patients either lack identifiable mutations or do not
respond to treatments targeting known mutations, suggesting that understanding genetic mutations alone and
using single-agent therapy is insufficient to overcome osimertinib resistance. However, there are currently no
animal models for studying osimertinib resistance-mediated brain metastases, which are essential for
understanding and targeting resistance mechanisms.
 The objective of this study is to develop an acquired osimertinib resistance model with resistance-mediated
brain metastases and circulating tumor cells (CTCs). Aim 1 will establish and characterize orthotopic NSCLC
models of acquired osimertinib resistance-mediated brain metastases using single-cell RNA sequencing. The
Wettersten laboratory also has access to whole-genome sequencing data from NSCLC patients with and without
prior osimertinib treatment. By comparing patient and mouse data, the study will identify common pathways that
are upregulated or downregulated in osimertinib-mediated brain metastases. The success of this aim will provide
a platform for testing therapeutic strategies to target osimertinib resistance-mediated brain metastases. Aim 2
will characterize CTCs from osimertinib-treated versus control NSCLC mouse models. The Wettersten lab has
previously developed an orthotopic NSCLC model for resistance to a first-generation EGFR inhibitor (erlotinib)
and resistance-mediated dissemination of CTCs. Using the same approach, CTCs from osimertinib-treated mice
will be isolated and analyzed. The success of this aim will provide osimertinib-mediated CTC models to identify
potential therapeutic targets for preventing new metastases.
 Given the limited efficacy of checkpoint inhibitors and the non-targeted nature of chemotherapy, there is a
critical need for novel therapeutics to address osimertinib-resistant NSCLC. Due to the heterogeneity of
osimertinib-resistant tumors, site-specific therapeutic approaches may be required for each metastasis site.
Additionally, it is crucial to predict the mechanisms of metastasis that patients may develop and target them
preemptively before resistant cells establish new tumors. The successful completion of this research will
generate well-characterized lung cancer mouse models with osimertinib resistance-mediated brain metastases,
as well as models to evaluate therapeutics for preventing the emergence of CTCs induced by osimertinib.

document fetched 2026-07-12 08:14