Virginia Commonwealth University (VCU) has received a USD 1.74 million National Cancer Institute R01 award to advance preclinical evaluation of PEPDG278D, a recombinant human protein designed to degrade both EGFR and HER2 in non-small cell lung cancer — including tumors resistant to approved tyrosine kinase inhibitors.
Drug resistance remains the central obstacle in EGFR-driven NSCLC. Third-generation TKIs such as osimertinib (Tagrisso) have improved outcomes for patients with mutated EGFR, but resistance develops in virtually all cases, often driven by HER2 co-activation and kinase-independent oncogenic signaling. PEPDG278D — an enzymatically inactive mutant of human peptidase D (prolidase) — is reported to bind the extracellular domains of both EGFR and HER2, triggering their degradation rather than simply blocking kinase activity. The hypothesis underlying the grant is that receptor degradation may prove more durable than kinase inhibition alone, since it eliminates both catalytic and non-catalytic oncogenic functions. The funded work will assess PEPDG278D across wild-type and mutant EGFR contexts, benchmark it against necitumumab (Portrazza) and osimertinib, and test combination strategies in osimertinib-resistant models.
The approach occupies a distinct mechanistic space from approved EGFR-directed agents. Necitumumab blocks EGFR ligand binding but has demonstrated limited efficacy. Osimertinib and earlier TKIs target the kinase domain but leave receptor protein intact. Antibody-drug conjugates such as patritumab deruxtecan (HER3-DXd) address resistance through payload delivery rather than receptor elimination. PEPDG278D's dual EGFR/HER2 degradation strategy has not been previously validated in clinical settings and remains at the preclinical stage.