ArticleTumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine2015
Loss of MLH1 confers resistance to PI3Kβ inhibitors in renal clear cell carcinoma with SETD2 mutation.
Article in Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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14 citing papers in PubMed, 26 citations in OpenAlex.
- Genomic loss of MLH1/PMS2 loci defines a mismatch repair deficient subgroup in monomorphic epitheliotropic intestinal T-cell lymphoma.Blood cancer journal · 2026Article
- Loss of SETD2 in wild-type VHL clear cell renal cell carcinoma sensitizes cells to STF-62247 and leads to DNA damage, cell cycle arrest, and cell death characteristic of pyroptosis.Molecular oncology · 2025Article
- The Evolving Molecular Landscape and Actionable Alterations in Urologic Cancers.Current oncology (Toronto, Ont.) · 2024Review
- Epigenetic modifiers: activities in renal cell carcinoma.Nature reviews. Urology · 2018Review
- Knockdown of tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein zeta (YWHAZ) enhances tumorigenesis both in vivo and in vitro in bladder cancer.Oncology reports · 2018Article
- Nutlin-3a as a novel anticancer agent for adrenocortical carcinoma with CTNNB1 mutation.Cancer medicine · 2018Article
- EZH2 Expression is increased in BAP1-mutant renal clear cell carcinoma and is related to poor prognosis.Journal of Cancer · 2018Article
- The Identification of Immunological Biomarkers in Kidney Cancers.Frontiers in oncology · 2018Review
- Overexpression of HSD17B4 exerts tumor suppressive function in adrenocortical carcinoma and is not associated with hormone excess.Oncotarget · 2017Article
- Epigallocatechin gallate inhibits the growth and promotes the apoptosis of bladder cancer cells.Experimental and therapeutic medicine · 2017Article
- SETting the Stage for Cancer Development: SETD2 and the Consequences of Lost Methylation.Cold Spring Harbor perspectives in medicine · 2017Review
- CLIP-GENE: a web service of the condition specific context-laid integrative analysis for gene prioritization in mouse TF knockout experiments.Biology direct · 2016Article
- Coexistence of YWHAZ amplification predicts better prognosis in muscle-invasive bladder cancer with CDKN2A or TP53 loss.Oncotarget · 2016Article
- Inhibition of pentose phosphate pathway suppresses acute myelogenous leukemia.Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine · 2016Article
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5 authors at 2 institutions in 1 country.
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No grant is acknowledged in the PubMed record.
Abstract
Renal clear cell carcinoma (ccRCC) is characterized by frequent mutation in SETD2, which has recently been shown to regulate mismatch repair (MMR). We aim to investigate the association between MMR machinery genes and SETD2 mutation in ccRCC. We exploited the Genomics of Drug Sensitivity in Cancer (GDSC) database to identify selective inhibitors for SETD2 mutant ccRCC cells. We also exploited the Cancer Genome Atlas (TCGA) database to study the association between SETD2 status and MMR-related genes. In vitro studies were performed to validate the in silico findings. Reproduction of the GDSC database revealed four compounds with significant selectivity for SETD2 mutant ccRCC cells, amongst which two compounds targeted PI3Kβ. Phosphorylation of AKT at both S473 and T308 was decreased following PI3Kβ inhibitor treatment in SETD2 mutant ccRCC cells, whereas the basal pAKT level was not changed between mutant and wild-type SETD2. Both decreased MLH1 and increased AKT levels induced lower PMS2, indicating that MMR was mediated by SETD2 via both AKT and MLH1 in ccRCC. Analysis of the TCGA database further revealed high tendency of homozygous co-deletion of SETD2 and MLH1. In the absence of MLH1, suppression of pAKT by PI3Kβ inhibitor was mitigated and inhibition in cell proliferation, invasiveness, migratory ability and tumourigenesis was partially restored. Besides the reported H3K36-trimethylation pathway, we found that SETD2 mutation also mediated MMR via AKT-induced PMS2 decrease and co-loss of MLH1 loss in ccRCC.
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