Scientists from Cancer Research UK have discovered a new combination of drugs which could start the self-destructive process of lung cancer cells. This finding paves the way for the research on new lung cancer therapy. Their study was published in Cell Death & Differentiation.

Tumor necrosis factor-related apoptosis-inducing ligand(TRAIL) can induce apoptosis in many cancer cells without causing toxicity in vivo. However, to date, TRAIL-receptor agonists have only shown limited therapeutic benefit in clinical trials.

In this study, researchers have identified PIK-75, a small molecule inhibitor of the p110αisoform of phosphoinositide-3 kinase(PI3K) as an exceptionally potent TRAIL apoptosis sensitizer. However, PI3K inhibition was not responsible for this activity. A kinome-side in vitro screen revealed that PIK-75 strongly inhibits a panel of 27 kinases in addition to p110α. Within this panel, they identified with TRAIL effectively induced apoptosis even in highly TRAIL-resistant cancer cells. In addition, When evaluating cancer selectivity of TRAIL combined with SNS-032, the most selective and clinically used inhibitior of CDK9, they found that a panel of mostly TRAIL-resistant non-small cell lung cancer cell lines was readily killed, even at low concentrations of TRAIL.

To sum up, based on the high potency of CDK9 inhibition as a cancer cell-selective TRAIL-sensitizing strategy, the researchers envisage the development of new, highly effective cancer therapies.

Reference:

Lemke J, von Karstedt S, El Hay M A, et al. Selective CDK9 inhibition overcomes TRAIL resistance by concomitant suppression of cFlip and Mcl-1[J]. Cell Death & Differentiation, 2013, 21(3): 491-502.