Effects of tumor-microbial interactions on EGFR-targeted therapy resistance in lung cancer - PROJECT SUMMARY/ABSTRACT
We are in desperate need of novel therapies for treating lung cancer, particularly ones that can overcome
treatment resistance. Intra-tumoral bacteria are emerging as a cause of therapy resistance in cancer. We
recently discovered that a specific bacteria, Chryseobacterium indologenes, identified within human lung
cancers, leads to resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI). The
third-generation EGFR-TKI osimertinib is the standard of care for first-line treatment of patients with advanced
EGFR-mutated lung cancer. Mechanisms of resistance to osimertinib are poorly understood. In this proposal we
seek to understand the mechanisms by which intra-tumoral Chryseobacterium (ITC) leads to resistance to
osimertinib. The long-term objective of this proposal is to develop new therapies targeting the effects of ITC to
prevent resistance to EGFR-TKIs. The objective of this proposal is to identify the mechanism responsible for
the effect of ITC on sensitivity to osimertinib, and to determine if other species of Chryseobacterium also lead to
EGFR-TKI resistance. Our central hypothesis is that ITC leads to resistance to osimertinib via secreted proteins
in some patients with EGFR-mutated lung cancer. In Aim 1, we will validate the candidate proteins that we
previously identified in Chryseobacterium preconditioned medium (C-PCM) as potentially responsible for
osimertinib resistance using fast protein liquid chromatography and mass spectrometry, by testing the purified
candidate proteins in EGFR-mutated lung cancer cell lines in the presence/absence of osimertinib. Next, we will
determine the mechanism by which ITC affects resistance to EGFR-TKIs, by investigating the effects of C-PCM
on (1) drug efflux, (2) re-activation of the EGFR pathway or (3) activation of molecular pathways other than
EGFR. These experiments will help us understand how Chryseobacterium indologenes leads to osimertinib,
allowing us to eventually develop new therapies to prevent or overcome osimertinib resistance. In Aim 2, we will
determine if Chryseobacterium species other than indologenes lead to EGFR-TKI resistance in PC9 cells. We
will obtain commercially available Chryseobacterium meningoseptica, angstadti, gleum, indoltheticum,
scophthalmum, diehli, shigense, and balustinum species which will be cultured and genotyped using PCR.
Preconditioned medium (PCM) from each species will then be serially diluted and added to PC9 cells with and
without osimertinib, and effects on cell growth will be determined using cell proliferation assays. These
experiments will help us understand which other Chryseobacterium species lead to osimertinib and may shed
additional light on mechanisms of osimertinib resistance. The proposed research is potentially transformative as
it may lead to the discovery of a new approach to overcoming resistance to EGFR-TKIs in patients with EGFR-
mutated lung cancer through targeting specific tumor-microbial interactions that lead to treatment resistance.
