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Response to MLN8237 in pancreatic cancer is not dependent on RalA phosphorylation

Nicole F Neel1, Jeran K Stratford, Vaishali Shinde

  • 1Corresponding Author: Jen Jen Yeh, The University of North Carolina at Chapel Hill, CB# 7213, 1150 Physicians Office Building, 101 Manning Drive, Chapel Hill, NC 27599-7213; jjyeh@med.unc.edu.

Molecular Cancer Therapeutics
|November 14, 2013
PubMed

Insights

Aurora A kinase inhibitor MLN8237 shows variable efficacy in pancreatic ductal adenocarcinoma (PDAC). RalA phosphorylation does not predict response, but Ki67 may serve as an early biomarker for MLN8237 treatment in PDAC patients.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Pancreatic ductal adenocarcinoma (PDAC) frequently harbors KRAS mutations, activating the RalGEF-Ral pathway.
  • Phosphorylation of RalA at S194 by Aurora A kinase (AAK) is crucial for PDAC tumorigenesis.
  • Targeting the AAK-RalA pathway presents a potential therapeutic strategy for PDAC.

Purpose of the Study:

  • To evaluate the efficacy of the AAK-selective inhibitor MLN8237 as an indirect anti-RalA therapy for PDAC.
  • To assess the correlation between RalA S194 phosphorylation and MLN8237 response in PDAC models.
  • To identify potential predictive biomarkers for MLN8237 treatment response in PDAC.

Main Methods:

  • Utilized a site-specific phospho-S194 RalA antibody to measure RalA phosphorylation levels in PDAC cell lines and patient tumors.
  • Assessed the effects of MLN8237 on anchorage-independent growth in PDAC cell lines and patient-derived xenografts (PDX).
  • Investigated Ki67 as a potential pharmacodynamic biomarker for MLN8237 response.

Main Results:

  • Elevated RalA S194 phosphorylation was observed in a subset of PDAC cell lines and tumors.
  • MLN8237 demonstrated variable efficacy, with a subset of cell lines and PDX models showing sensitivity.
  • RalA S194 phosphorylation levels did not correlate with MLN8237 responsiveness.
  • Ki67 emerged as a potential early predictive biomarker for MLN8237 response.

Conclusions:

  • MLN8237 may be effective in a subset of PDAC patients irrespective of RalA S194 phosphorylation status.
  • Ki67 shows promise as a pharmacodynamic biomarker for early prediction of MLN8237 treatment response in PDAC.
  • Further investigation into AAK inhibitors and predictive biomarkers is warranted for PDAC therapy.

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