Genetics of renal cancer: focus on MTOR

Academic Article


  • Renal cell carcinoma (RCC) has multiple subtypes and may occur in hereditary and sporadic forms. Sporadicrenal cell carcinomas are most commonly clear cellcancers (80%). Metastatic disease is found atpresentation in almost 30% of patients with renal cellcarcinoma and treatment of RCC metastases is greatlydifferent from the treatment regimens of the primarytumor. Currently, several FDA approved therapies existfor metastatic clear cell RCC (ccRCC) which includestwo rapamycin analogs-everolimus and temsirolimus.The mammalian target of rapamycin (mTOR) is aserine/threonine kinase and catalytic subunit of twobiochemically distinct complexes called mTORC1 andmTORC2. Recently published TCGA data reportaberrations in the PI3K/AKT/mTOR pathway in up to28% of RCC cases [1]. Whether these aberrationspredict for clinical benefit of mTOR-targeted therapy inccRCC patients is debatable. Prior studies haveidentified hyperactivating point mutations in mTOR thatremain sensitive to rapamycin [2] while other recentstudies have identified a somatic mutation in mTORthat is resistant to allosteric mTOR inhibition whileremaining sensitive to mTOR kinase inhibitors [3].Mutations in MTOR are clustered in various regulatorydomains in ccRCC. We focused our attention on aprominent cluster of hyperactivating mutations in theFAT (FRAP–ATM–TTRAP) domain of mTOR inccRCC that led to an increase in both mTORC1 andmTORC2 activities and led to an increased proliferationof cells [4]. Several of the FAT domain mutantsdemonstrated a decreased binding of the intrinsicinhibitor DEPTOR (DEP domain containing mTORinteractingprotein), while a subset of these mutationsshowed altered binding of the negative regulatorPRAS40 (proline rich AKT substrate 40). We alsoidentified a recurrent mutation in RHEB (Ras homologenriched in brain) in ccRCC patients that exclusivelyincreased mTORC1 activity. Interestingly, mutations inthe FAT domain of MTOR and in RHEB remainedsensitive to rapamycin, though several of thesemutations demonstrated residual mTOR kinase activityafter treatment with rapamycin at clinically relevantdoses. Overall, our data suggests that point mutations inthe mTOR pathway may lead to downstream mTORhyperactivation through multiple different mechanismsto confer a proliferative advantage to a tumor cell
  • Published In

  • Aging  Journal
  • Digital Object Identifier (doi)

    Author List

  • Ghosh AP; Sudarshan S
  • Start Page

  • 421
  • End Page

  • 422
  • Volume

  • 8
  • Issue

  • 3