Induced degradation of lineage-specific oncoproteins drives the therapeutic vulnerability of small cell lung cancer to PARP inhibitors

Author:

Kim Chiho12ORCID,Wang Xu-Dong12ORCID,Liu Zhengshuai12ORCID,Hao Jianwei2ORCID,Wang Shuai1ORCID,Li Peng1ORCID,Zi Zhenzhen1ORCID,Ding Qing1,Jang Seoyeon3ORCID,Kim Jiwoong4ORCID,Luo Yikai5ORCID,Huffman Kenneth E.6,Pal Choudhuri Shreoshi6,del Rio Sofia2ORCID,Cai Ling4,Liang Han5ORCID,Drapkin Benjamin J.6ORCID,Minna John D.6ORCID,Yu Yonghao12ORCID

Affiliation:

1. Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.

2. Department of Molecular Pharmacology and Therapeutics, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA.

3. Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.

4. Quantitative Biomedical Research Center, Department of Population and Data Sciences, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.

5. Department of Bioinformatics and Computational Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

6. Hamon Center for Therapeutic Oncology Research, Simmons Comprehensive Cancer Center, Departments of Internal Medicine and Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.

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.

Publisher

American Association for the Advancement of Science (AAAS)

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