Targeting SRC family kinases in lung cancer

Abstract

Lung cancer is the commonest cancer killer worldwide. This is mainly due to the rapid development of drug resistance and early metastatic dissemination of the disease. SRC family kinases (SFKs) are frequently over-expressed in various cancers and have been implicated in tumorigenesis through their ability to promote cancer cell proliferation, survival and invasiveness. Therefore, we sought to evaluate the involvement of SFKs in lung cancer biology and assess the possible therapeutic benefits of their inhibition, either alone or in combination with additional treatments. We demonstrate that SRC family kinases are over-expressed and activated in-vitro in a panel of lung cancer cell lines as compared to immortalised normal lung epithelial cells. SRC, FYN and LYN are expressed in a high proportion of lung cancer but not normal lung tissue sections. Furthermore, enhanced expression of LYN correlates with poor patients’ survival. Dasatinib is a novel SRC/ABL inhibitor which effectively blocks SFKs activity at nanomolar concentrations. Dasatinib reduces cell numbers in 10 out of 11 NSCLC cell lines tested, which correlates with a strong inhibition of DNA synthesis and cell proliferation, while apoptosis is moderately enhanced only in a few cell lines. Interestingly, dasatinib potently induces autophagy in all NSCLC cell lines tested. This appears to be a pro-survival mechanism as autophagy inhibition using chemical compounds or siRNA-mediated depletion of ATG5 sensitises NSCLC cells to dasatinib through enhanced apoptosis. Lastly, our results indicate that SFKs have both overlapping and isoform-specific functions in NSCLC cell biology, as demonstrated by the effects of siRNA-mediated knockdown of SRC, YES, FYN or LYN. Our results suggest that inhibition of SRC family kinases alone or in combination with autophagy inhibitors may be a beneficial therapeutic strategy in the management of lung cancer patients