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

Autor: Kim C; Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.; Department of Molecular Pharmacology and Therapeutics, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA., Wang XD; Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.; Department of Molecular Pharmacology and Therapeutics, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA., Liu Z; Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.; Department of Molecular Pharmacology and Therapeutics, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA., Hao J; Department of Molecular Pharmacology and Therapeutics, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA., Wang S; Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA., Li P; Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA., Zi Z; Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA., Ding Q; Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA., Jang S; Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA., Kim J; Quantitative Biomedical Research Center, Department of Population and Data Sciences, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA., Luo Y; Department of Bioinformatics and Computational Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA., Huffman KE; 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., Pal Choudhuri S; 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., Del Rio S; Department of Molecular Pharmacology and Therapeutics, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA., Cai L; Quantitative Biomedical Research Center, Department of Population and Data Sciences, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA., Liang H; Department of Bioinformatics and Computational Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA., Drapkin BJ; 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., Minna JD; 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., Yu Y; Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.; Department of Molecular Pharmacology and Therapeutics, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA.
Jazyk: angličtina
Zdroj: Science advances [Sci Adv] 2024 Jan 19; Vol. 10 (3), pp. eadh2579. Date of Electronic Publication: 2024 Jan 19.
DOI: 10.1126/sciadv.adh2579
Abstrakt: 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.
Databáze: MEDLINE