Evaluating rational non-cross-resistant combination therapy in advanced clear cell renal cell carcinoma: Combined mTOR and AKT inhibitor therapy

William S. Holland, Clifford G Tepper, Jose E. Pietri, Danielle C. Chinn, David R Gandara, Philip Mack, Primo N Lara

Research output: Contribution to journalArticle

13 Scopus citations

Abstract

Purpose: Inhibition of the mammalian target of rapamycin (mTOR), a regulator of hypoxia inducible factor (HIF), is an established therapy for advanced renal cell cancer (RCC). Inhibition of mTOR results in compensatory AKT activation, a likely resistance mechanism. We evaluated whether addition of the Akt inhibitor perifosine to the mTOR inhibitor rapamycin would synergistically inhibit RCC. Methods: Select RCC cell lines were studied [786-O, A498 (VHL mutant), CAKI-1 (VHL wild type), and 769-P (VHL methylated)] with single agent and combination therapy. Growth inhibition was assessed by MTT and cell cycling by flow cytometry. Phospho-AKT (S473) and HIF-2α were assessed by Western blot. Total RNA was isolated from 786-O cells subjected to single agent and combination treatments. In these cells, genome-wide expression profiles were assessed, and real-time PCR was used to confirm a limited set of expression results. Results: Three out of four cell lines (CAKI-1, 769-P, and 786-O) were sensitive to single-agent perifosine with 50% inhibitory concentrations ranging from 5 to 10 μM. Perifosine blocked phosphorylation of AKT induced by rapamycin and inhibited HIF-2α expression in 786-O and CAKI-1. Combined treatment resulted in sub-additive growth inhibition. GeneChip analysis and pathway modeling revealed inhibition of the IL-8 pathway by these agents, concomitant with up-regulation of the KLF2 gene, a known suppressor of HIF1α. Conclusions: Perifosine is active in select RCC lines, abrogating the induction of AKT phosphorylation mediated by mTOR inhibition. Combined mTOR and AKT inhibition resulted in the modulation of pro-angiogenesis pathways, providing a basis for future investigations.

Original languageEnglish (US)
Pages (from-to)185-194
Number of pages10
JournalCancer Chemotherapy and Pharmacology
Volume69
Issue number1
DOIs
StatePublished - Jan 2012

Keywords

  • AKT
  • mTOR
  • Perifosine
  • Rapamycin
  • Renal cell cancer

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Pharmacology
  • Pharmacology (medical)
  • Toxicology

Fingerprint Dive into the research topics of 'Evaluating rational non-cross-resistant combination therapy in advanced clear cell renal cell carcinoma: Combined mTOR and AKT inhibitor therapy'. Together they form a unique fingerprint.

  • Cite this