Bosutinib inhibits migration and invasion via ack1 in kras mutant non-small cell lung cancerReport as inadecuate




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Molecular Cancer

, 13:13

First Online: 24 January 2014Received: 24 September 2013Accepted: 21 January 2014DOI: 10.1186-1476-4598-13-13

Cite this article as: Tan, D.S., Haaland, B., Gan, J.M. et al. Mol Cancer 2014 13: 13. doi:10.1186-1476-4598-13-13

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.

KeywordsLung cancer ACK1 KRAS Bosutinib Metastasis AbbreviationsACK1Activated Cdc42 associated kinase 1

UBAUbiquitin association domain

EGFREpidermal growth factor receptor

RCCRenal clear cell carcinoma

EMTEpithelial-mesenchymal transition

TNFTumor necrosis factor

HSP60Heat shock protein 60.

Electronic supplementary materialThe online version of this article doi:10.1186-1476-4598-13-13 contains supplementary material, which is available to authorized users.

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