Research Papers:

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

Robert E. Brown, Jamie Buryanek, Varaha S. Tammisetti, Mary F. McGuire and Keri Csencsits-Smith _

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Oncotarget. 2016; 7:41612-41621. https://doi.org/10.18632/oncotarget.9508

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Robert E. Brown1, Jamie Buryanek1, Varaha S. Tammisetti2, Mary F. McGuire1, Keri Csencsits-Smith1

1Department of Pathology and Laboratory Medicine, The University of Texas Health Science Center at Houston McGovern Medical School, TX 77030, Houston, USA

2Diagnostic and Interventional Imaging, The University of Texas Health Science Center at Houston McGovern Medical School, TX 77030, Houston, USA

Correspondence to:

Keri Csencsits-Smith, email: Keri.C.Smith@uth.tmc.edu

Keywords: renal cell carcinoma, rapalog therapy, immunohistochemistry, MTORC2, resistance

Received: November 11, 2015     Accepted: April 16, 2016     Published: May 20, 2016


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.

Design: 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.

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