Selective CDK9 inhibition overcomes TRAIL resistance in NSCLC
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can induce apoptosis in cancer cells without causing toxicity in vivo. However, to date TRAIL-receptor agonists have shown only limited therapeutic benefit in clinical trials. This can, most likely, be attributed to the fact that most primary human cancers are TRAIL-resistant. Hence, future TRAIL-based therapies will require the addition of sensitizing agents that remove crucial blocks in the TRAIL apoptosis pathway.
PIK-75 strongly sensitises cancer cells to TRAIL-induced apoptosis independently of inhibition of p110?. We performed a kinome-wide screen to identify which kinases were inhibited by PIK-75. To evaluate which of the 27 kinases inhibited was responsible for PIK-75-mediated sensitization to TRAIL-induced apoptosis, we screened all 27 kinases identified by siRNA knockdown. We next assessed the potency of SNS-032 (the clinically used inhibitor of CDK9) and TRAIL combination in vitro in a panel of NSCLC cell lines and in vivo using an orthotopic model of lung cancer.
We identified CDK9, a PIK-75-target, to be responsible for TRAIL resistance of cancer cells. The combination of CDK9 inhibition with TRAIL effectively induced apoptosis even in highly TRAIL-resistant cancer cells. Mechanistically, CDK9 inhibition resulted in the downregulation of cFlip and Mcl-1, at both the mRNA and protein levels. Furthermore, we found that a panel of mostly TRAIL-resistant NSCLC cell lines was readily killed by the combination of TRAIL and SNS-032, even at low concentrations of TRAIL. Importantly, primary human hepatocytes did not succumb to the same treatment regime, defining a therapeutic window for the combination of TRAIL with CDK9 inhibitors. Importantly, the combination of SNS-032 and TRAIL was also highly effective in vivo and led to eradication of established orthotopic NSCLC tumors.
Based on the high potency of CDK9 inhibition as a cancer cell-selective TRAIL-sensitizing strategy, we envisage the development of new, highly effective cancer therapies.
We would like to gratefully acknowledge Theo Giannopoulos and Susanne Booth at Castle Hill Hospital for their help in acquiring ovarian tissue samples, and Jane Smales for coordinating the clinical aspects of the study. This study is funded by a grant from NC3Rs (Registry File: G1100600).
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