Loss of the endocytic tumor suppressor HD-PTP phenocopies LKB1 and promotes RAS-driven oncogenesis.

Autor: Seong CS; Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA USA., Huang C; Cancer Animal Models Shared Resource, Winship Cancer Institute of Emory University, Atlanta, GA, USA., Boese AC; Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA USA.; Cancer Biology Graduate Program, Laney Graduate School, Emory University, Atlanta, GA, USA., Hou Y; Cancer Animal Models Shared Resource, Winship Cancer Institute of Emory University, Atlanta, GA, USA., Koo J; Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA USA., Mouw JK; Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA USA., Rupji M; Biostatistics Shared Resource, Winship Cancer Institute of Emory University, Atlanta, GA, USA., Joseph G; Data and Technology Applications Shared Resource, Winship Cancer Institute of Emory University, Atlanta, GA, USA., Johnston HR; Emory Integrated Computational Core, Emory University, Atlanta, GA., Claussen H; Emory Integrated Computational Core, Emory University, Atlanta, GA., Switchenko JM; Biostatistics Shared Resource, Winship Cancer Institute of Emory University, Atlanta, GA, USA., Behera M; Data and Technology Applications Shared Resource, Winship Cancer Institute of Emory University, Atlanta, GA, USA., Churchman M; M2Gen, Tampa, FL, USA., Kolesar JM; Markey Cancer Center, University of Kentucky, Lexington, KY, USA., Arnold SM; Markey Cancer Center, University of Kentucky, Lexington, KY, USA., Kerrigan K; Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA., Akerley W; Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA., Colman H; Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA., Johns MA; Winship Cancer Institute of Emory University, Atlanta, GA, USA., Arciero C; Department of Surgery, Emory University School of Medicine, Atlanta, GA USA., Zhou W; Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA USA.; Winship Cancer Institute of Emory University, Atlanta, GA, USA., Marcus AI; Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA USA.; Winship Cancer Institute of Emory University, Atlanta, GA, USA., Ramalingam SS; Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA USA.; Winship Cancer Institute of Emory University, Atlanta, GA, USA., Fu H; Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA USA.; Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA, USA., Gilbert-Ross M; Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA USA.; Winship Cancer Institute of Emory University, Atlanta, GA, USA.
Jazyk: angličtina
Zdroj: BioRxiv : the preprint server for biology [bioRxiv] 2023 Jan 27. Date of Electronic Publication: 2023 Jan 27.
DOI: 10.1101/2023.01.26.525772
Abstrakt: Oncogenic RAS mutations drive aggressive cancers that are difficult to treat in the clinic, and while direct inhibition of the most common KRAS variant in lung adenocarcinoma (G12C) is undergoing clinical evaluation, a wide spectrum of oncogenic RAS variants together make up a large percentage of untargetable lung and GI cancers. Here we report that loss-of-function alterations (mutations and deep deletions) in the gene that encodes HD-PTP ( PTPN23 ) occur in up to 14% of lung cancers in the ORIEN Avatar lung cancer cohort, associate with adenosquamous histology, and occur alongside an altered spectrum of KRAS alleles. Furthermore, we show that in publicly available early-stage NSCLC studies loss of HD-PTP is mutually exclusive with loss of LKB1, which suggests they restrict a common oncogenic pathway in early lung tumorigenesis. In support of this, knockdown of HD-PTP in RAS-transformed lung cancer cells is sufficient to promote FAK-dependent invasion. Lastly, knockdown of the Drosophila homolog of HD-PTP (dHD-PTP/Myopic) synergizes to promote RAS-dependent neoplastic progression. Our findings highlight a novel tumor suppressor that can restrict RAS-driven lung cancer oncogenesis and identify a targetable pathway for personalized therapeutic approaches for adenosquamous lung cancer.
Databáze: MEDLINE