Bosutinib inhibits migration and invasion via ACK1 in KRAS mutant non-small cell lung cancer.
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.
Daniel S W
DS
Tan
Benjamin
B
Haaland
Jia Min
JM
Gan
Su Chin
SC
Tham
Indrajit
I
Sinha
Eng Huat
EH
Tan
Kiat Hon
KH
Lim
Angela
A
Takano
Sai Sakktee
SS
Krisna
Minn Minn Myint
MM
Thu
Hoe Peng
HP
Liew
Axel
A
Ullrich
Wan-Teck
WT
Lim
Singapore OncoGenome Laboratory, Institute of Medical Biology, Agency of Science Technology and Research, Singapore, Singapore. btchua@imcb.a-star.edu.sg.
Boon Tin
BT
Chua
D000814:Aniline Compounds / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009154:Mutation; D009361:Neoplasm Invasiveness / Q000473:pathology; D009570:Nitriles / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D011804:Quinolines / Q000494:pharmacology*; D060888:Real-Time Polymerase Chain Reaction; D046888:Tissue Array Analysis; D023041:Xenograft Model Antitumor Assays; D015027:Zebrafish; D018631:ras Proteins / Q000235:genetics*
D000814:Aniline Compounds; D000970:Antineoplastic Agents; C117307:KRAS protein, human; D009570:Nitriles; D011518:Proto-Oncogene Proteins; D011804:Quinolines; C471992:bosutinib; D011505:Protein-Tyrosine Kinases; C403262:TNK2 protein, human; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins