Targeting Degradation of EGFR through the Allosteric Site Leads to Cancer Cell Detachment-Promoted Death
Abstract
Targeting epidermal growth factor receptor (EGFR) with tyrosine kinase inhibitors (TKI)
has been widely exploited to disrupt aberrant phosphorylation flux in cancer. However, a bottleneck
of potent TKIs is the acquisition of drug resistance mutations, secondary e ects, and low ability
to attenuate tumor progression. We have developed an alternative means of targeting EGFR
that relies on protein degradation through two consecutive routes, ultimately leading to cancer
cell detachment-related death. We describe furfuryl derivatives of 4-allyl-5-[2-(4-alkoxyphenyl)-
quinolin-4-yl]-4H-1,2,4-triazole-3-thiol that bind to and weakly inhibit EGFR tyrosine phosphorylation
and induce strong endocytic degradation of the receptor in cancer cells. The compound-promoted
depletion of EGFR resulted in the sequestration of non-phosphorylated Bim, which no longer ensured
the integrity of the cytoskeleton machinery, as shown by the detachment of cancer cells from the
extracellular matrix (ECM). Of particular note, the longer CH3(CH2)n chains in the terminal moiety of
the anti-EGFR molecules confer higher hydrophobicity in the allosteric site located in the immediate
vicinity of the catalytic pocket. Small compounds accelerated and enhanced EGFR and associated
proteins degradation during EGF and/or glutamine starvation of cultures, thereby demonstrating
high potency in killing cancer cells by simultaneously modulating signaling and metabolic pathways.
We propose a plausiblemechanismof anti-cancer action by small degraders through the allosteric site of
EGFR. Our data represent a rational and promising perspective in the treatment of aggressive tumors.
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Origin : Publication funded by an institution
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