Loss of the endocytic tumor suppressor HD-PTP phenocopies LKB1 and promotes RAS-driven oncogenesis.
Seong, C.-S.; Huang, C.; Boese, A. C.; Hou, Y.; Koo, J.; Mouw, J. K.; Rupji, M.; Joseph, G.; Johnston, H. R.; Claussen, H.; Switchenko, J. M.; Behera, M.; Churchman, M.; Kolesar, J. M.; Arnold, S. M.; Kerrigan, K.; Akerley, W.; Colman, H.; Johns, M. A.; Arciero, C.; Zhou, W.; Marcus, A. I.; Ramalingam, S. S.; Fu, H.; Gilbert-Ross, M.
Show abstract
Abstract/SummaryOncogenic 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.
Matching journals
The top 9 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Th17 cells contribute to combination MEK inhibitor and anti-PD-L1 therapy resistance in KRAS/p53 mutant lung cancers 96%
- Identification of DLK1, a Notch ligand, as an immunotherapeutic target and regulator of tumor cell plasticity and chemoresistance in adrenocortical carcinoma 96%
- Melanoblast transcriptome analysis reveals novel pathways promoting melanoma metastasis 96%
Similar papers in this journal
Similar papers in this journal
- Distinct Nrf2 Signaling Thresholds Mediate Lung Tumor Initiation and Progression 95%
- Epigenomic profiling discovers trans-lineage SOX2 partnerships driving tumor heterogeneity in lung squamous cell carcinoma 95%
- Pharmacologically targeting KRASG12D in PDAC models:tumor cell intrinsic and extrinsic impact 95%
Similar papers in this journal
- DARPP-32 promotes ERBB3-mediated resistance to molecular targeted therapy in EGFR-mutated lung adenocarcinoma 96%
- Inhibition of the YAP-MMB interaction and targeting NEK2 as potential therapeutic strategies for YAP-driven cancers 95%
- Colon Cancer Cells Evade Drug Action by Enhancing Drug Metabolism 95%
Similar papers in this journal
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.