Proteasome-Independent Protein Knockdown by Small-Molecule Inhibitor for the Undruggable Lung Adenocarcinoma

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Lung adenocarcinoma (LUAD) treatment faces challenges, particularly the aggressive proximal-proliferative subtype lacking druggable mutations.
• Leucine-rich pentatricopeptide repeat-containing protein (LRPPRC) is identified as a novel tumor driver overexpressed in lethal LUAD subtypes.
• Current therapeutic strategies struggle with targeting proteins like LRPPRC, which localize to mitochondria and are degraded independently of the proteasome.

Purpose of the Study:

• To identify novel therapeutic targets for aggressive lung adenocarcinoma.
• To develop a new strategy for targeted protein knockdown beyond proteasomal degradation.
• To screen for small molecules that induce LRPPRC degradation via mitochondrial proteases.

Main Methods:

• A cell-SELEX-generated aptamer was used to identify LRPPRC as a specific target.
• An aptamer-assisted high-throughput screening method was developed to find small molecules binding LRPPRC.
• Gossypolacetic acid (GAA) was identified as a compound that disrupts LRPPRC-chaperone interaction, leading to mitochondrial degradation.

Main Results:

• LRPPRC was confirmed as a specific and overexpressed protein in the most malignant LUAD subtype.
• Gossypolacetic acid (GAA) effectively induced LRPPRC knockdown by promoting its degradation through mitochondrial proteases.
• GAA demonstrated significant antitumor effects in LRPPRC-positive patient-derived tumor xenograft models.

Conclusions:

• Targeted LRPPRC knockdown represents a promising therapeutic strategy for previously undruggable lung adenocarcinoma.
• Aptamer-based screening offers a viable approach for identifying inhibitors against undruggable cancer targets.
• This study presents a novel strategy for protein knockdown, circumventing proteasome-dependent degradation pathways.