title: Mechanistically distinct cancer-associated mTOR activation clusters predict sensitivity to rapamycin.
abstract: Genomic studies have linked mTORC1 pathway-activating mutations with exceptional response to treatment with allosteric inhibitors of mTORC1 called rapalogs. Rapalogs are approved for selected cancer types, including kidney and breast cancers. Here, we used sequencing data from 22 human kidney cancer cases to identify the activating mechanisms conferred by mTOR mutations observed in human cancers and advance precision therapeutics. mTOR mutations that clustered in focal adhesion kinase targeting domain (FAT) and kinase domains enhanced mTORC1 kinase activity, decreased nutrient reliance, and increased cell size. We identified 3 distinct mechanisms of hyperactivation, including reduced binding to DEP domain-containing MTOR-interacting protein (DEPTOR), resistance to regulatory associated protein of mTOR-mediated (RAPTOR-mediated) suppression, and altered kinase kinetics. Of the 28 mTOR double mutants, activating mutations could be divided into 6 complementation groups, resulting in synergistic Rag- and Ras homolog enriched in brain-independent (RHEB-independent) mTORC1 activation. mTOR mutants were resistant to DNA damage-inducible transcript 1-mediated (REDD1-mediated) inhibition, confirming that activating mutations can bypass the negative feedback pathway formed between HIF1 and mTORC1 in the absence of von Hippel-Lindau (VHL) tumor suppressor expression. Moreover, VHL-deficient cells that expressed activating mTOR mutants grew tumors that were sensitive to rapamycin treatment. These data may explain the high incidence of mTOR mutations observed in clear cell kidney cancer, where VHL loss and HIF activation is pathognomonic. Our study provides mechanistic and therapeutic insights concerning mTOR mutations in human diseases.
authors.forename: Jianing
authors.initials: J
authors.lastname: Xu
authors.forename: Can G
authors.initials: CG
authors.lastname: Pham
authors.forename: Steven K
authors.initials: SK
authors.lastname: Albanese
authors.forename: Yiyu
authors.initials: Y
authors.lastname: Dong
authors.forename: Toshinao
authors.initials: T
authors.lastname: Oyama
authors.forename: Chung-Han
authors.initials: CH
authors.lastname: Lee
authors.forename: Vanessa
authors.initials: V
authors.lastname: Rodrik-Outmezguine
authors.forename: Zhan
authors.initials: Z
authors.lastname: Yao
authors.forename: Song
authors.initials: S
authors.lastname: Han
authors.forename: David
authors.initials: D
authors.lastname: Chen
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Parton
authors.forename: John D
authors.initials: JD
authors.lastname: Chodera
authors.forename: Neal
authors.initials: N
authors.lastname: Rosen
authors.forename: Emily H
authors.initials: EH
authors.lastname: Cheng
authors.forename: James J
authors.initials: JJ
authors.lastname: Hsieh
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D002292:Carcinoma, Renal Cell / Q000188:drug therapy / Q000235:genetics; D004249:DNA Damage; D005260:Female; D015894:Genome, Human; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy / Q000235:genetics*; D007700:Kinetics; D008297:Male; D051379:Mice; D016513:Mice, SCID; D056004:Molecular Dynamics Simulation; D009154:Mutation; D020125:Mutation, Missense; D010957:Plasmids / Q000378:metabolism; D000072417:Protein Domains; D034741:RNA, Small Interfering / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000378:metabolism
chemical_list: D000903:Antibiotics, Antineoplastic; D034741:RNA, Small Interfering; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; C497446:VHL protein, human; D020123:Sirolimus