ZFIN ID: ZDB-PUB-140321-39
Bosutinib inhibits migration and invasion via ack1 in kras mutant non-small cell lung cancer
Tan, D.S., Haaland, B., Gan, J.M., Tham, S.C., Sinha, I., Tan, E.H., Lim, K.H., Takano, A., Krisna, S.S., Thu, M.M., Liew, H.P., Ullrich, A., Lim, W.T., and Chua, B.T.
Date: 2014
Source: Molecular Cancer   13(1): 13 (Journal)
Registered Authors: Liew, Hoe Peng, Sinha, Indrajit
Keywords: none
MeSH Terms:
  • Aniline Compounds/pharmacology*
  • Animals
  • Antineoplastic Agents/pharmacology*
  • Blotting, Western
  • Carcinoma, Non-Small-Cell Lung/genetics
  • Carcinoma, Non-Small-Cell Lung/metabolism*
  • Carcinoma, Non-Small-Cell Lung/pathology
  • Cell Line, Tumor
  • Cell Movement/drug effects
  • Gene Knockdown Techniques
  • Humans
  • Lung Neoplasms/genetics
  • Lung Neoplasms/metabolism*
  • Lung Neoplasms/pathology
  • Mutation
  • Neoplasm Invasiveness/pathology
  • Nitriles/pharmacology*
  • Protein-Tyrosine Kinases/metabolism*
  • Proto-Oncogene Proteins/genetics*
  • Quinolines/pharmacology*
  • Real-Time Polymerase Chain Reaction
  • Tissue Array Analysis
  • Xenograft Model Antitumor Assays
  • Zebrafish
  • ras Proteins/genetics*
PubMed: 24461128 Full text @ Mol. Cancer
FIGURES
ABSTRACT

The advent of effective targeted therapeutics has led to increasing emphasis on precise biomarkers for accurate patient stratification. Here, we describe the role of ACK1, a non-receptor tyrosine kinase in abrogating migration and invasion in KRAS mutant lung adenocarcinoma. Bosutinib, which inhibits ACK1 at 2.7 nM IC50, was found to inhibit cell migration and invasion but not viability in a panel of non-small cell lung cancer (NSCLC) cell lines. Knockdown of ACK1 abrogated bosutinib-induced inhibition of cell migration and invasion specifically in KRAS mutant cells. This finding was further confirmed in an in vivo zebrafish metastatic model. Tissue microarray data on 210 Singaporean lung adenocarcinomas indicate that cytoplasmic ACK1 was significantly over-expressed relative to paired adjacent non-tumor tissue. Interestingly, ACK1 expression in “normal” tissue adjacent to tumour, but not tumour, was independently associated with poor overall and relapse-free survival. In conclusion, inhibition of ACK1 with bosutinib attenuates migration and invasion in the context of KRAS mutant NSCLC and may fulfil a therapeutic niche through combinatorial treatment approaches.

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