title: Morphoproteomics and biomedical analytics confirm the mTORC2/Akt pathway as a resistance signature and activated ERK and STAT3 as concomitant prosurvival/antiapoptotic pathways in metastatic renal cell carcinoma (RCC) progressing on rapalogs: pathogenesis and therapeutic options.
abstract: BACKGROUND
  It has been proposed that resistance to rapalog therapies in renal cell carcinoma (RCC) is due to adaptive switching from mammalian target of rapamycin complex 1 (mTORC1) to mTORC2.
  
  
  OBJECTIVE
  To combine phosphoprotein staining and applied biomedical analytics to investigate resistance signatures in patients with metastatic RCC progressing on rapalog therapies.
  
  
  METHODS
  We applied morphoproteomic analysis to biopsy specimens from nine patients with metastatic RCC who continued to show clinical progression of their tumors while being treated with a rapalog.
  
  
  RESULTS
  In patients who were on temsirolimus or everolimus at the time of biopsy, a moderate to strong expression of phosphorylated (p)-mTOR (Ser 2448) in the nuclear compartment with concomitant expression of p-Akt (Ser 473) confirmed the mTORC2 pathway. Concomitant moderate to strong nuclear expression of p-ERK 1/2 (Thr202/Tyr204) and p-STAT3 (Tyr705) was confirmed. Histopathologic changes of hypoxic-type coagulative necrosis in 5 cases as well as identification of insulin-like growth factor-1 receptor (IGF-1R) expression and histone methyltransferase EZH2 in all tumors studied suggested that hypoxia also contributed to the resistance signature. Biomedical analytics provided insight into therapeutic options that could target such adaptive and pathogenetic mechanisms.
  
  
  CONCLUSIONS
  Morphoproteomics and biomedical analytics confirm mTORC2/Akt as a resistance signature to rapalog therapy in metastatic RCC and demonstrate activation of the prosurvival ERK and STAT3 pathways and involvement of hypoxic pathways that contribute to pathogenesis of such adaptive resistance. These results highlight the need for a novel combinatorial therapeutic approach in metastatic RCC progressing on rapalogs.
authors.affiliation: Department of Pathology and Laboratory Medicine, The University of Texas Health Science Center at Houston McGovern Medical School, TX 77030, Houston, USA.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Brown
authors.affiliation: Department of Pathology and Laboratory Medicine, The University of Texas Health Science Center at Houston McGovern Medical School, TX 77030, Houston, USA.
authors.forename: Jamie
authors.initials: J
authors.lastname: Buryanek
authors.affiliation: Diagnostic and Interventional Imaging, The University of Texas Health Science Center at Houston McGovern Medical School, TX 77030, Houston, USA.
authors.forename: Varaha S
authors.initials: VS
authors.lastname: Tammisetti
authors.affiliation: Department of Pathology and Laboratory Medicine, The University of Texas Health Science Center at Houston McGovern Medical School, TX 77030, Houston, USA.
authors.forename: Mary F
authors.initials: MF
authors.lastname: McGuire
authors.affiliation: Department of Pathology and Laboratory Medicine, The University of Texas Health Science Center at Houston McGovern Medical School, TX 77030, Houston, USA.
authors.forename: Keri
authors.initials: K
authors.lastname: Csencsits-Smith
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D002292:Carcinoma, Renal Cell / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D048429:Cell Size / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D019295:Computational Biology / Q000379:methods; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm; D004789:Enzyme Activation / Q000187:drug effects; D000068338:Everolimus / Q000627:therapeutic use; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D020869:Gene Expression Profiling / Q000379:methods; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D000076225:Mechanistic Target of Rapamycin Complex 2 / Q000378:metabolism; D009362:Neoplasm Metastasis; D051058:Oncogene Protein v-akt / Q000378:metabolism; D040901:Proteomics / Q000379:methods*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000627:therapeutic use; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C401859:temsirolimus; D000068338:Everolimus; D000076225:Mechanistic Target of Rapamycin Complex 2; D051058:Oncogene Protein v-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D020123:Sirolimus
keywords: MTORC2; immunohistochemistry; rapalog therapy; renal cell carcinoma; resistance