Induced Degradation of Lineage-Specific Oncoproteins Drives the Therapeutic Vulnerability of Small Cell Lung Cancer to PARP Inhibitors

Authors

Chiho Kim
Xu-Dong Wang
Zhengshuai Liu
Jianwei Hao
Shuai Wang
Peng Li
Zhenzhen Zi
Qing Ding
Seoyeon Jang
Jiwoong Kim
Yikai Luo
Kenneth E Huffman
Shreoshi Pal Choudhuri
Sofia Del Rio
Ling Cai
Han Liang
Benjamin J Drapkin
John D Minna
Yonghao Yu

Publication Date

1-19-2024

Journal

Science Advances

Abstract

Although BRCA1/2 mutations are not commonly found in small cell lung cancer (SCLC), a substantial fraction of SCLC shows clinically relevant response to PARP inhibitors (PARPis). However, the underlying mechanism(s) of PARPi sensitivity in SCLC is poorly understood. We performed quantitative proteomic analyses and identified proteomic changes that signify PARPi responses in SCLC cells. We found that the vulnerability of SCLC to PARPi could be explained by the degradation of lineage-specific oncoproteins (e.g., ASCL1). PARPi-induced activation of the E3 ligase HUWE1 mediated the ubiquitin-proteasome system (UPS)-dependent ASCL1 degradation. Although PARPi induced a general DNA damage response in SCLC cells, this signal generated a cell-specific response in ASCL1 degradation, leading to the identification of HUWE1 expression as a predictive biomarker for PARPi. Combining PARPi with agents targeting these pathways markedly improved therapeutic response in SCLC. The degradation of lineage-specific oncoproteins therefore represents a previously unidentified mechanism for PARPi efficacy in SCLC.

Keywords

Humans, Small Cell Lung Carcinoma, Lung Neoplasms, BRCA1 Protein, Poly(ADP-ribose) Polymerase Inhibitors, Proteomics, BRCA2 Protein, Oncogene Proteins, Cell Line, Tumor, Tumor Suppressor Proteins, Ubiquitin-Protein Ligases

DOI

10.1126/sciadv.adh2579

PMID

38241363

PMCID

PMC10798557

PubMedCentral® Posted Date

1-19-2024

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes