Discovery of a novel EGFR ligand DPBA that degrades EGFR and suppresses EGFR-positive NSCLC growth

Abstract

Epidermal growth factor receptor (EGFR) activation plays a pivotal role in EGFR-driven non-small cell lung cancer (NSCLC) and is considered as a key target of molecular targeted therapy. EGFR tyrosine kinase inhibitors (TKIs) have been canonically used in NSCLC treatment. However, prevalent innate and acquired resistances and EGFR kinase-independent pro-survival properties limit the clinical efficacy of EGFR TKIs. Therefore, the discovery of novel EGFR degraders is a promising approach towards improving therapeutic efficacy and overcoming drug resistance. Here, we identified a 23-hydroxybetulinic acid derivative, namely DPBA, as a novel EGFR small-molecule ligand. It exerted potent in vitro and in vivo anticancer activity in both EGFR wild type and mutant NSCLC by degrading EGFR. Mechanistic studies disclosed that DPBA binds to the EGFR extracellular domain at sites differing from those of EGF and EGFR. DPBA did not induce EGFR dimerization, phosphorylation, and ubiquitination, but it significantly promoted EGFR degradation and repressed downstream survival pathways. Further analyses showed that DPBA induced clathrin-independent EGFR endocytosis mediated by flotillin-dependent lipid rafts and unaffected by EGFR TKIs. Activation of the early and late endosome markers rab5 and rab7 but not the recycling endosome marker rab11 was involved in DPBA-induced EGFR lysosomal degradation. The present study offers a new EGFR ligand for EGFR pharmacological degradation and proposes it as a potential treatment for EGFR-positive NSCLC, particularly NSCLC with innate or acquired EGFR TKI resistance. DPBA can also serve as a chemical probe in the studies on EGFR trafficking and degradation.

STAMBP promotes lung adenocarcinoma metastasis by regulating the EGFR/MAPK signaling pathway

“…Thus, the manipulation of EGFR stability is an alternative therapy. EGFR degradation has been induced by various strategies, including delivering EGFR-specific siRNAs [ 50 , 51 ], proteolysis-targeting chimera (PROTAC) technology [52] and small molecular drugs [ 53 , 54 ]. Our findings that STAMBP knockdown promotes EGFR degradation and suppresses LUAD tumor metastasis raise the possibility that targeting STAMBP may be a promising strategy to control LUAD progression.…”

Disruptin, a cell-penetrating peptide degrader of EGFR

“…Induction of EGFR degradation remains an effective approach against EGFR-TKI resistant tumors [19] . We developed Disruptin peptide that binds with EGFR, blocks EGFR dimerization, and promotes EGFR degradation [15] .…”

Multidimensional Analysis of CHMP Family Members in Hepatocellular Carcinoma

“… 11–13 Besides the classical degradation pathway that relies on EGF induction, EGF-independent proteasomal degradation plays a major regulatory role in maintaining EGFR protein homeostasis. 14 , 15 The EGF–EGFR complex is internalized into the cell and passes through early endosomes, late endosomes, and multivesicular bodies (MVBs) before reaching the lysosome, where it is degraded, thereby attenuating the EGFR-mediated signal. 16 , 17 Endosomal sorting complexes required for transport (ESCRT) are involved in this process, sorting the ubiquitinated receptor at the MVB to facilitate lysosomal degradation.…”