Nanoscale Mapping of EGFR and c‑MET Protein Environments on Lung Cancer Cell Surfaces via Therapeutic Antibody Photocatalyst Conjugates

Receptor tyrosine kinases are involved in essential signaling
roles
that impact cell growth, differentiation, and proliferation. The overexpression
or mutation of these proteins can lead to aberrant signaling that
has been directly linked to a number of diseases including cancer
cell formation and progression. This has led to intense clinical focus
on modulating RTK activity through direct targeting of signaling activity
or cell types harboring aberrant RTK behavior. In particular, epidermal
growth factor receptor (EGFR) has attracted intense clinical attention
due to the impact of inhibiting this RTK on tumor growth. However,
mutations incurred through targeting EGFR have led to therapeutic
resistance that involves not only direct mutations to the EGFR protein
but also the involvement of other RTKs, such as c-MET, that can overcome
therapeutic-based EGFR inhibition effects. This has, not surprisingly,
led to co-targeting strategies of RTKs such as EGFR and c-MET to overcome
resistance mechanisms. While the ability to co-target these proteins
has led to success in the clinic, a more comprehensive understanding
of their proximal environments, particularly in the context of therapeutic
modalities, could further enhance both our understanding of their
signaling biology and provide additional avenues for targeting these
surface proteins. Thus, to investigate EGFR and c-MET protein microenvironments,
we utilized our recently developed iridium photocatalyst-based microenvironment
mapping technology to catalog EGFR and c-MET surface environments
on non-small cell lung cancer cell lines. Through this approach, we
enriched EGFR and c-MET from the cell surface and identified known
EGFR and c-MET associators as well as previously unidentified proximal
proteins.