Response to MLN8237 in pancreatic cancer is not dependent on RalA phosphorylation.
The high prevalence of KRAS mutations and importance of the RalGEF-Ral pathway downstream of activated K-ras in pancreatic ductal adenocarcinoma (PDAC) emphasize the importance of identifying novel methods by which to therapeutically target these pathways. It was recently demonstrated that phosphorylation of RalA S194 by Aurora A kinase (AAK) is critical for PDAC tumorigenesis. We sought to evaluate the AAK-selective inhibitor MLN8237 as a potential indirect anti-RalA-targeted therapy for PDAC. We used a site-specific phospho-S194 RalA antibody and determined that RalA S194 phosphorylation levels were elevated in a subset of PDAC cell lines and human tumors relative to unmatched normal controls. Effects of MLN8237 on anchorage-independent growth in PDAC cell lines and growth of patient-derived xenografts (PDX) were variable, with a subset of cell lines and PDX showing sensitivity. Surprisingly, RalA S194 phosphorylation levels in PDAC cell lines or PDX tumors did not correlate with MLN8237 responsiveness. However, we identified Ki67 as a possible early predictive biomarker for response to MLN8237 in PDAC. These results indicate that MLN8237 treatment may be effective for a subset of patients with PDAC independent of RalA S194 phosphorylation. Ki67 may be an effective pharmacodynamic biomarker to identify response early in the course of treatment.
Corresponding 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.
Nicole F
NF
Neel
Jeran K
JK
Stratford
Vaishali
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Shinde
Jeffrey A
JA
Ecsedy
Timothy D
TD
Martin
Channing J
CJ
Der
Jen Jen
JJ
Yeh
D064096:Aurora Kinase A / Q000378:metabolism; D001381:Azepines / Q000008:administration & dosage*; D014408:Biomarkers, Tumor / Q000235:genetics; D063646:Carcinogenesis / Q000187:drug effects*; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D006801:Humans; D019394:Ki-67 Antigen / Q000235:genetics*; D009154:Mutation; D010766:Phosphorylation / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D011743:Pyrimidines / Q000008:administration & dosage*; D020725:ral GTP-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D018631:ras Proteins / Q000235:genetics
D001381:Azepines; D014408:Biomarkers, Tumor; C117307:KRAS protein, human; D019394:Ki-67 Antigen; C550258:MLN 8237; D011518:Proto-Oncogene Proteins; D011743:Pyrimidines; D064096:Aurora Kinase A; C492198:RALA protein, human; D016283:Proto-Oncogene Proteins p21(ras); D020725:ral GTP-Binding Proteins; D018631:ras Proteins