ArticleBreast cancer research : BCR2018
Functional genomics identifies specific vulnerabilities in PTEN-deficient breast cancer.
Article in Breast cancer research : BCR, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed, 21 citations in OpenAlex.
- NUAK: never underestimate a kinase.Essays in biochemistry · 2024Review
- Synthetic lethal approaches to target cancers with loss of PTEN function.Genes & diseases · 2023Article
- NUAK1 governs centrosome replication in pancreatic cancer via MYPT1/PP1β and GSK3β-dependent regulation of PLK4.Molecular oncology · 2023Article
- Co-occurrence of BAP1 and SF3B1 mutations in uveal melanoma induces cellular senescence.Molecular oncology · 2022Article
- Identification of ZG16B as a prognostic biomarker in breast cancer.Open medicine (Warsaw, Poland) · 2021Article
- Laboratory Models for Investigating Breast Cancer Therapy Resistance and Metastasis.Frontiers in oncology · 2021Review
- WDHD1 is essential for the survival of PTEN-inactive triple-negative breast cancer.Cell death & disease · 2020Article
- Phosphatidylinositol-3-OH kinase signalling is spatially organized at endosomal compartments by microtubule-associated protein 4.Nature cell biology · 2020Article
- Article
- CTCF loss mediates unique DNA hypermethylation landscapes in human cancers.Clinical epigenetics · 2020Article
- Article
- PI3Kβ-A Versatile Transducer for GPCR, RTK, and Small GTPase Signaling.Endocrinology · 2019Review
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9 authors at 3 institutions in 1 country.
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Abstract
backgroundPhosphatase and tensin homolog (PTEN) is one of the most frequently inactivated tumor suppressors in breast cancer. While PTEN itself is not considered a druggable target, PTEN synthetic-sick or synthetic-lethal (PTEN-SSL) genes are potential drug targets in PTEN-deficient breast cancers. Therefore, with the aim of identifying potential targets for precision breast cancer therapy, we sought to discover PTEN-SSL genes present in a broad spectrum of breast cancers.
methodsTo discover broad-spectrum PTEN-SSL genes in breast cancer, we used a multi-step approach that started with (1) a genome-wide short interfering RNA (siRNA) screen of ~ 21,000 genes in a pair of isogenic human mammary epithelial cell lines, followed by (2) a short hairpin RNA (shRNA) screen of ~ 1200 genes focused on hits from the first screen in a panel of 11 breast cancer cell lines; we then determined reproducibility of hits by (3) identification of overlaps between our results and reanalyzed data from 3 independent gene-essentiality screens, and finally, for selected candidate PTEN-SSL genes we (4) confirmed PTEN-SSL activity using either drug sensitivity experiments in a panel of 19 cell lines or mutual exclusivity analysis of publicly available pan-cancer somatic mutation data.
resultsThe screens (steps 1 and 2) and the reproducibility analysis (step 3) identified six candidate broad-spectrum PTEN-SSL genes (PIK3CB, ADAMTS20, AP1M2, HMMR, STK11, and NUAK1). PIK3CB was previously identified as PTEN-SSL, while the other five genes represent novel PTEN-SSL candidates. Confirmation studies (step 4) provided additional evidence that NUAK1 and STK11 have PTEN-SSL patterns of activity. Consistent with PTEN-SSL status, inhibition of the NUAK1 protein kinase by the small molecule drug HTH-01-015 selectively impaired viability in multiple PTEN-deficient breast cancer cell lines, while mutations affecting STK11 and PTEN were largely mutually exclusive across large pan-cancer data sets.
conclusionsSix genes showed PTEN-SSL patterns of activity in a large proportion of PTEN-deficient breast cancer cell lines and are potential specific vulnerabilities in PTEN-deficient breast cancer. Furthermore, the NUAK1 PTEN-SSL vulnerability identified by RNA interference techniques can be recapitulated and exploited using the small molecule kinase inhibitor HTH-01-015. Thus, NUAK1 inhibition may be an effective strategy for precision treatment of PTEN-deficient breast tumors.
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