title: Loss of MLH1 confers resistance to PI3Kβ inhibitors in renal clear cell carcinoma with SETD2 mutation.
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.
authors.affiliation: Department of Urology, Huashan Urology, Fudan University, 12 Central Urumqi Rd, Shanghai, 200040, People's Republic of China.
authors.forename: Chenchen
authors.initials: C
authors.lastname: Feng
authors.forename: Guanxiong
authors.initials: G
authors.lastname: Ding
authors.forename: Haowen
authors.initials: H
authors.lastname: Jiang
authors.forename: Qiang
authors.initials: Q
authors.lastname: Ding
authors.forename: Hui
authors.initials: H
authors.lastname: Wen
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000502:physiology; D002292:Carcinoma, Renal Cell / Q000188:drug therapy / Q000235:genetics*; D045744:Cell Line, Tumor; D053843:DNA Mismatch Repair; D019008:Drug Resistance, Neoplasm; D017353:Gene Deletion; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics*; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy / Q000235:genetics*; D000070957:MutL Protein Homolog 1; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics* / Q000502:physiology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011495:Histone-Lysine N-Methyltransferase; C521636:SETD2 protein, human; D051057:Proto-Oncogene Proteins c-akt; D000070957:MutL Protein Homolog 1